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Search Results

APP (58)

APP encodes amyloid precursor protein, a transmembrane protein which is cleaved to form amyloidogenic Aβ peptides. Mutations in APP are associated with familial forms of early onset Alzheimer's disease as well as with Cerebral Amyloid Angiopathy (CAA). Pathogenic mutations generally alter processing by secretases, leading in an overall increase in Aβ production and/or a change in the ratio of specific Aβ peptides.

Mutation Clinical
Phenotype
Pathogenicity Neuropathology Biological Effect Genomic Position Genomic Region Mutation Type
Codon Change
Research
Models
Primary
Papers
A201V
None, Parkinson's Disease Dementia AD : Not Pathogenic Not applicable. Unknown; predicted tolerated in silico.

rs149995579
Coding
Exon 5
Point, Missense
GCG to GTG
0 Sassi et al., 2014
A235V
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Unknown.

Coding
Exon 6
Point, Missense
GCT to GTT
0 Nicolas et al., 2015
D243N
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Unknown.

Coding
Exon 6
Point, Missense
GAT to AAT
0 Nicolas et al., 2015
E246K
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Unknown; predicted probably damaging in silico.

rs147485129
Coding
Exon 6
Point, Missense
GAG to AAG
0 Sala Frigerio et al., 2015
E296K
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Unknown.

Coding
Exon 7
Point, Missense
GAG to AAG
0 Nicolas et al., 2015
P299L
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Unknown.

Coding
Exon 7
Point, Missense
CCG to CTG
0 Nicolas et al., 2015
R468H
None AD : Not Pathogenic Not applicable. Unknown.

Coding
Exon 11
Point, Missense
CGC to CAC
0 Schulte et al., 2015
A479S
None AD : Not Pathogenic Not applicable. Unknown; predicted benign in silico.

rs143794560
Coding
Exon 11
Point, Missense
GCT to TCT
0 Sala Frigerio et al., 2015
K496Q
Alzheimer's Disease AD : Unclear Pathogenicity One reported carrier of this variant had autopsy-confirmed AD. Unknown; predicted possibly damaging in silico.

rs201384815
Coding
Exon 12
Point, Missense
AAG to CAG
0 Sassi et al., 2014
A500T
None AD : Not Pathogenic Not applicable. Unknown.

rs201547994
Coding
Exon 12
Point, Missense
GCA to ACA
0 Schulte et al., 2015
Y538H
Alzheimer's Disease AD : Not Pathogenic Neuropathology consistent with AD, but not thought to be attributed to this variant. Unknown; predicted possibly damaging in silico.

Coding
Exon 13
Point, Missense
TAT to CAT
0 Sassi et al., 2014
V562I
None AD : Not Pathogenic Not applicable. Unknown; predicted tolerated in silico.

rs199586073
Coding
Exon 13
Point, Missense
GTT to ATT
0 Sassi et al., 2014
E599K
None, Parkinson's Disease, Parkinson's Disease Dementia AD : Not Pathogenic Not applicable. Unknown; predicted possibly damaging in silico.

rs140304729
Coding
Exon 14
Point, Missense
GAA to AAA
0 Sassi et al., 2014
T600M
None AD : Not Pathogenic Not applicable. Unknown.

rs200088099
Coding
Exon 14
Point, Missense
ACG to ATG
0 Schulte et al., 2015
P620A
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Unknown.

Coding
Exon 14
Point, Missense
CCG to GCG
0 Nicolas et al., 2015
P620L
Alzheimer's Disease AD : Not Pathogenic One reported carrier of the variant had autopsy-confirmed AD.  Unknown; predicted tolerated in silico.

Coding
Exon 14
Point, Missense
CCG to CTG
0 Sassi et al., 2014
T663M
Parkinson's Disease Dementia AD : Not Pathogenic, PDD : Unclear Pathogenicity Unknown. Unknown.

rs200260102
Coding
Exon 16
Point, Missense
ACG to ATG
0 Schulte et al., 2015
E665D
None AD : Not Pathogenic Not applicable. Unknown.

rs63750363
Coding
Exon 16
Point, Missense
GAG to GAC
0 Peacock et al., 1994
KM670/671NL
(Swedish)
Alzheimer's Disease AD : Pathogenic Generalized atrophy with sulcal widening and mild ventricular enlargement. Increased total Aβ; unchanged Aβ42/Aβ40 ratio; increased production and secretion of Aβ42 and Aβ40.

rs63751263, rs63750445
Coding
Exon 16
Point, Double
AAG.ATG to AAT.CTG
65 Mullan et al., 1992
A673T
(Icelandic)
None AD : Protective This variant is associated with minimal amyloid deposition and is thought to protect against amyloid pathology. Reduced production of amyloidogenic Aβ peptides by about 40 percent. The Aβ generated is less prone to aggregation.

rs63750847
Coding
Exon 16
Point, Missense
GCA to ACA
0 Peacock et al., 1993;
Jonsson et al., 2012
A673V
Alzheimer's Disease AD : Pathogenic Definite AD by CERAD criteria, with extensive deposition of Aβ and tau pathology (Braak stage VI). Cerebral amyloid angiopathy. Deposits contained high levels of Aβ40 and were noted to be unusually large, with few preamyloid deposits. Localization was frequently perivascular. In vitro, A673V shifts β-secretase processing of APP toward the amyloidogenic pathway and increases Aβ aggregation; however, co-incubation of mutant and wild-type Aβ inhibits amyloidogenesis and toxicity.

Coding
Exon 16
Point, Missense
GCA to GTA
0 Di Fede et al., 2009
H677R
(English)
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Accelerated oligomerization kinetics and greater cytotoxicity than wild-type Aβ.

rs63749953
Coding
Exon 16
Point, Missense
CAT to CGT
0 Janssen et al., 2003
D678H
(Taiwanese)
Alzheimer's Disease AD : Pathogenic Unknown; SPECT imaging showed hypoperfusion in the bilateral parietal cortices and the left temporal lobe. Increased Aβ42/Aβ40 ratio in conditioned media; increased secreted Aβ42 and Aβ40. When coincubated with Cu2+ and Zn2+, mutant Aβ exhibits increased metal ion binding and formation of ion-induced Aβ oligomers. Increased toxicity in vitro compared with wild-type Aβ42.

Coding
Exon 16
Point, Missense
GAC to CAC
0 Chen et al., 2012
D678N
(Tottori)
Alzheimer's Disease AD : Pathogenic Marked cortical atrophy, Bilateral hippocampal atrophy, Absence of focal cerebral infarction or hemorrhagic lesions. Accelerated oligomerization kinetics and greater cytotoxicity than wild-type Aβ.

rs63750064
Coding
Exon 16
Point, Missense
GAC to AAC
0 Wakutani et al., 2004
E682K
(Leuven)
Alzheimer's Disease AD : Pathogenic Bilateral hippocampal volume loss; Cortical PiB uptake. Significantly increased total Aβ and Aβ42/Aβ40 levels; Shifts BACE1 cleavage toward the β-site.

Coding
Exon 16
Point, Missense
GAA to AAA
0 Zhou et al., 2011
K687N
Alzheimer's Disease AD : Pathogenic Unknown; MRI showed mild global brain atrophy without focal or vascular lesions. CSF biomarker profile consistent with AD, specifically elevated total tau and phosphorylated tau, along with reduced levels of Aβ1-42. Reduces APP cleavage by α-secretase. Reduced production of total sAPP and especially sAPPα. Increased Aβ40 and Aβ42. Alone, mutant Aβ was less toxic to neuroblastoma cells than wild-type Aβ42, but mixed in equimolar amounts with wild-type, toxicity increased. Alone, mutant Aβ formed predominantly low-n oligomers in vitro, but mixed with wild-type Aβ, it aggregated into high-n oliogmers.

Coding
Exon 16
Point, Missense
AAA to AAT
0 Kaden et al., 2012
A692G
(Flemish)
Alzheimer's Disease AD : Pathogenic β-amyloid deposition in the blood vessels of the brain; Numerous senile plaques; Dystrophic neurites; Congophilic angiopathy; Hemorrhagic infarction. Increased secreted Aβ42 and Aβ40 in CHO, HEK-293, and H4 cells; Altered APP processing.

rs63750671
Coding
Exon 17
Point, Missense
GCA to GGA
0 Hendriks et al., 1992
E693del
(Osaka, E693∆, E693delta)
Alzheimer's Disease AD : Pathogenic Unknown; remarkably low levels of amyloid by PiB-PET imaging. Unchanged Aβ42/Aβ40 ratio; decreased Aβ42; decreased Aβ40; Mutant Aβ more resistant to degradation by neprilysin and insulin-degrading enzyme; Synthetic mutant Aβ had enhanced oligomerization but no fibrillization; Greater inhibition of LTP than wild-type Aβ.

Coding
Exon 17
Deletion
GAA to ---
1 Tomiyama et al., 2008
E693G
(Arctic, E22G)
Alzheimer's Disease AD : Pathogenic No signs of strokes or vascular lesions by brain imaging; Neuritic plaques and neurofibrillary tangles. Arctic Aβ40 forms protofibrils at an increased propensity and faster rate; Decreased proteolytic degradation of Aβ by neprilysin.

rs63751039
Coding
Exon 17
Point, Missense
GAA to GGA
5 Kamino et al., 1992;
Nilsberth et al., 2001
E693K
(Italian)
Cerebral Amyloid Angiopathy CAA : Pathogenic Small to large hematomas, subarachnoid bleeding, scars with hemosiderin deposits, small infarcts; Aβ immunoreactivity in vessel walls and neuropil; Absence of neurofibrillary changes and neuritic plaques. Reduced Aβ42/Aβ40 ratio; decreased Aβ42; comparable Aβ40 to wild-type APP.

rs63750579
Coding
Exon 17
Point, Missense
GAA to AAA
0 Tagliavini et al., 1999;
Bugiani et al., 2010
E693Q
(Dutch)
Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch type CAA : Pathogenic Extensive amyloid deposition in the cerebral vasculature; Hemorrhages; Some diffuse plaques in brain parenchyma. Accelerates Aβ aggregation in vitro, increasing fibril formation; Alters the processing of APP, increasing the relative quantities of Aβ beginning at Asp1, Val18, and Phe19.

rs63750579
Coding
Exon 17
Point, Missense
GAA to CAA
4 Levy et al., 1990;
Van Broeckhoven et al., 1990;
Fernandez-Madrid et al., 1991
D694N
(Iowa)
Alzheimer's Disease, Cerebral Amyloid Angiopathy AD : Pathogenic, CAA : Pathogenic Extensive cerebral amyloid angiopathy; Widespread neurofibrillary tangles; Abundant Aβ40 in plaques; Hemorrhagic lesions; Cortical calcifications in the occipital lobe. Increased fibrillogenesis of the Aβ peptide; Greater Aβ-induced toxicity.

rs63749810
Coding
Exon 17
Point, Missense
GAT to AAT
2 Grabowski et al., 2001
L705V
Cerebral Amyloid Angiopathy CAA : Pathogenic Severe CAA; Hemorrhages originating from affected vessels; “Vessel-within-vessel” morphology; Absence of parenchymal amyloid deposits and neurofibrillary tangles. Unknown.

rs63750921
Coding
Exon 17
Point, Missense
CTC to GTC
0 Obici et al., 2005
G708G
None AD : Not Pathogenic Not applicable. Unknown.

rs148888161
Coding
Exon 17
Point, Silent
GGC to GGT
0 Balbín et al., 1992
G709S
Parkinson's Disease Dementia AD : Not Pathogenic, PDD : Unclear Pathogenicity Unknown. Unknown.

rs201269325
Coding
Exon 17
Point, Missense
GGT to AGT
0 Schulte et al., 2015
A713T
Alzheimer's Disease, Cerebral Amyloid Angiopathy, None AD : Pathogenic, CAA : Pathogenic Variable: Generalized atrophy of the cerebral cortex; Widespread neurofibrillary tangles; Neuritic plaques; Variable cerebral amyloid angiopathy. Unchanged Aβ42/Aβ40 ratio in postmortem brain.

rs63750066
Coding
Exon 17
Point, Missense
GCG to ACG
0 Carter et al., 1992;
Armstrong et al., 2004
A713V
None AD : Not Pathogenic Not applicable. Unknown.

rs1800557
Coding
Exon 17
Point, Missense
GCG to GTG
0 Jones et al., 1992
T714A
(Iranian)
Alzheimer's Disease AD : Pathogenic Progressive cortical atrophy; White matter lesions. Unknown.

rs63750643
Coding
Exon 17
Point, Missense
ACA to GCA
0 Pasalar et al., 2002
T714I
(Austrian)
Alzheimer's Disease AD : Pathogenic Extensive neuronal loss; Diffuse gliosis; Neurofibrillary tangles; Amyloid plaques including diffuse "cloudy" plaques. Increased Aβ42/Aβ40 ratio (about 11-fold); increased Aβ42; decreased Aβ40.

rs63750973
Coding
Exon 17
Point, Missense
ACA to ATA
1 Kumar-Singh et al., 2000
V715A
(German)
Alzheimer's Disease AD : Pathogenic Hypoperfusion in the parieto-occipital region. Increased Aβ42/Aβ40 ratio.

rs63750868
Coding
Exon 17
Point, Missense
GTG to GCG
0 Cruts et al., 2003
V715M
(French)
Alzheimer's Disease AD : Pathogenic Progressive cortical atrophy; Hypometabolism. Decreased total Aβ; unchanged Aβ42; significantly decreased Aβ40.

rs63750734
Coding
Exon 17
Point, Missense
GTG to ATG
0 Ancolio et al., 1999
I716F
(Iberian)
Alzheimer's Disease AD : Pathogenic Extensive mixed neuropathology, including neurofibrillary changes, amyloid deposits, and Lewy bodies. Increased Aβ42/Aβ40 ratio; increased Aβ42; decreased Aβ40; Increased APP C-terminal fragments; Decreased production of APP intracellular domain.

Coding
Exon 17
Point, Missense
ATC to TTC
2 Guerreiro et al., 2010
I716M
Alzheimer's Disease AD : Pathogenic Unknown; MRI showed mild bilateral hippocampal atrophy. Unknown; predicted damaging in silico.

Coding
Exon 17
Point, Missense
ATC to ATG
0 Blauwendraat et al., 2016
I716T
Alzheimer's Disease AD : Pathogenic Unknown. Unknown.

rs63750851
Coding
Exon 17
Point, Missense
ATC to ACC
0 Terreni et al., 2002
I716V
(Florida)
Alzheimer's Disease AD : Pathogenic Diffuse cortical atrophy, most prominant in the left anterior temporal lobe. Increased Aβ42(43)/Aβ40 ratio; increased Aβ42(43).

rs63750399
Coding
Exon 17
Point, Missense
ATC to GTC
10 Eckman et al., 1997
V717F
(Indiana)
Alzheimer's Disease AD : Pathogenic Unknown. Increased Aβ42/Aβ40 ratio.

rs63750264
Coding
Exon 17
Point, Missense
GTC to TTC
13 Murrell et al., 1991
V717G
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD in at least one case. Increased Aβ42/Aβ40 ratio; increased Aβ42; decreased Aβ40.

rs63749964
Coding
Exon 17
Point, Missense
GTC to GGC
0 Chartier-Harlin et al., 1991
V717I
(London)
Alzheimer's Disease AD : Pathogenic Variable: some reports of mild amyloid angiopathy and cortical and brainstem Lewy bodies, along with numerous plaques and tangles. Increased Aβ42/Aβ40 ratio; increased Aβ42; little effect on Aβ40.

rs63750264
Coding
Exon 17
Point, Missense
GTC to ATC
22 Goate et al., 1991
V717L
Alzheimer's Disease AD : Pathogenic Unknown; MRI in the Japanese family showed relatively minor atrophic changes in the bilateral hippocampus and cerebral cortices. Increased Aβ42/Aβ40 ratio; increased Aβ42; decreased Aβ40.

rs63750264
Coding
Exon 17
Point, Missense
GTC to CTC
0 Murrell et al., 2000
T719P
Alzheimer's Disease AD : Pathogenic Unknown; atrophy of the temporal lobes by MRI. Reduced total Aβ in CSF, especially Aβ1-40 and Aβ1-42 with a relative increase in Aβ1-38.

Coding
Exon 17
Point, Missense
ACC to CCC
0 Ghidoni et al., 2009
M722K
Alzheimer's Disease, None AD : Pathogenic Unknown; MRI of the proband at age 42 showed moderate cerebral atrophy, especially in the hippocampus. Increase Aβ42/Aβ40 ratio; increased Aβ42; unchanged Aβ40; More phospho-tau.

Coding
Exon 17
Point, Missense
ATG to AAG
0 Wang et al., 2015
L723P
(Australian)
Alzheimer's Disease AD : Pathogenic Unknown. Increased Aβ42 in CHO cells.

rs63751122
Coding
Exon 17
Point, Missense
CTG to CCG
0 Kwok et al., 2000
K724N
(Belgian)
Alzheimer's Disease AD : Pathogenic Significant amyloid across the cerebral cortex as measured by PiB-PET. Increased Aβ42/Aβ40 ratio; increased Aβ42; decreased Aβ40.

rs63750151
Coding
Exon 17
Point, Missense
AAG to AAC
0 Theuns et al., 2006
H733P
None AD : Not Pathogenic Not applicable. Unknown.

Coding
Exon 17
Point, Missense
CAT to CCT
0 Guerreiro et al., 2010
IVS17 83-88delAAGTAT
Alzheimer's Disease, None AD : Unclear Pathogenicity Unknown; at least one affected deletion carrier had neuropathology consistent with AD. Unknown; deletion does not appear to affect APP splicing.

rs367709245
Non-Coding
Intron 17
Deletion
0 Kamino et al., 1992
c.*18 C>T
Cerebral Amyloid Angiopathy CAA : Unclear Pathogenicity Unknown; imaging showed an ischemic stroke in the right middle cerebral artery and hematomas in the right temporal and parietal lobes. MRI showed numerous cortical microbleeds and  white-matter hyperintensities. Unknown.

rs201729239
Non-Coding
3' UTR
Point
0 Nicolas et al., 2015
c.*331_*332del
Cerebral Amyloid Angiopathy CAA : Pathogenic Unknown; imaging revealed multiple subarachnoid hemorrhages and hematomas in the temporal, frontal, and parietal regions of the cortex, as well as diffuse superficial siderosis, cortical microbleeds, and white matter hyperintensities. This deletion of two base pairs (TA) occurs in a highly conserved region of  the UTR. When cloned into a luciferase reporter, the variant increased APP expression (~1.5-fold over WT). APP upregulation was at least partially attributable to changes in miRNA binding.

Non-Coding
3' UTR
Deletion
0 Nicolas et al., 2015
c.*372 A>G
Cerebral Amyloid Angiopathy CAA : Not Pathogenic Unknown; at least two mutation carriers had hemorrhages and microbleeds consistent with CAA. However, this variant has also been detected in controls. Unknown.

rs187940037
Non-Coding
3' UTR
Point
0 Nicolas et al., 2015

MAPT (108)

MAPT encodes the microtubule associated protein tau, a protein central to Alzheimer’s disease neuropathology. MAPT mutations are not linked to familial forms of AD, but can cause frontotemporal dementia (FTD) and several other tauopathies. The pathogenic mutations, which can be either exonic or intronic, generally alter the relative production of tau isoforms and lead to changes in microtubule assembly and/or the propensity of tau to aggregate.

Mutation Clinical
Phenotype
Pathogenicity Neuropathology Biological Effect Genomic Position Genomic Region Mutation Type
Codon Change
Research
Models
Primary
Papers
P4T
None AD : Not Pathogenic Not applicable. Unknown; predicted probably damaging in silico.

Coding
Exon 1
Point, Missense
CCC to ACC
0 Sala Frigerio et al., 2015
R5C
Parkinson's Disease Dementia PDD : Unclear Pathogenicity Unknown. Unknown.

Coding
Exon 1
Point, Missense
CGC to TGC
0 Schulte et al., 2015
R5H
Frontotemporal Dementia FTD : Unclear Pathogenicity, AD : Unclear Pathogenicity Neuronal loss in the frontal and temporal lobes; Tau deposits predominantly in glia, progressive supranuclear palsy-like straight tubules; Accumulation of 4-repeat (4R), Sarkosyl-insoluble tau.   Reduces tau's ability to promote microtubule assembly; Increases fibril formation in vitro.

rs63750959
Coding
Exon 1
Point, Missense
CGC to CAC
0 Hayashi et al., 2002
R5L
Progressive Supranuclear Palsy Other Tauopathy : Pathogenic Aggregated insoluble tau in subcortical regions was predominantly 4-repeat (4R) tau with 0 or 1 amino terminal inserts (i.e. 0N4R or 1N4R). Insoluble tau in cortical regions also contained 1N3R tau. Reduces tau's ability to promote microtubule assembly; No effect on the ratio of tau isoforms synthesized.

rs63750959
Coding
Exon 1
Point, Missense
CGC to CTC
0 Poorkaj et al., 2002
H14H
None FTD : Not Pathogenic Not applicable. Unknown.

Coding
Exon 1
Point, Silent
CAC to CAT
0 Guerreiro et al., 2010
T17M
None FTD : Not Pathogenic Not applicable. In silico analysis predicted a possible effect on protein function.

rs144611688
Coding
Exon 1
Point, Missense
ACG to ATG
0 Guerreiro et al., 2010
Y18Y
None FTD : Not Pathogenic Not applicable. Unknown.

rs63750811
Coding
Exon 1
Point, Silent
TAC to TAT
0 Houlden et al., 1999;
Guerreiro et al., 2010
T30A
None FTD : Not Pathogenic Not applicable. Unknown.

Coding
Exon 1
Point, Missense
ACC to GCC
0 Guerreiro et al., 2010
T39T
None FTD : Unclear Pathogenicity Unknown. Unknown.

rs63750529
Coding
Exon 1
Point, Silent
ACG to ACA
0 Houlden et al., 1999
A41T
Parkinson's Disease PD : Unclear Pathogenicity Unknown. Unknown.

rs115239819
Coding
Exon 1
Point, Missense
GCT to ACT
0 Schulte et al., 2015
G55R
Frontotemporal Dementia FTD : Pathogenic Unknown; frontal and temporal atrophy by MRI. In vitro 4-repeat (4R) tau with the G55R mutation nucleates microtubule assembly more effectively than wild-type 4R tau. This effect appears to be isoform-specific, and was not seen in 3R tau.

Coding
Exon 2
Point, Missense
GGA to AGA
0 Iyer et al., 2013
V75A
Frontotemporal Dementia FTD : Unclear Pathogenicity Frontotemporal atrophy and fronto-mesial and parietal left hypoperfusion. Unknown.

Coding
Exon 3
Point, Missense
GTG to GCG
0 Gallo et al., 2010
G86S
None FTD : Unclear Pathogenicity Frontal hypometabolism by PET. No effect on normal splicing of exons 2 or 3; Creation of a predicted phosphorylation site and a predicted O-glycosylation site.

rs63751135
Coding
Exon 3
Point, Missense
GGC to AGC
0 Stanford et al., 2004
A90V
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Unknown; predicted benign in silico.

Coding
Exon 3
Point, Missense
GCC to GTC
0 Sala Frigerio et al., 2015
A152T
CBD, Alzheimer's Disease, Dementia with Lewy Bodies, Frontotemporal Dementia, Progressive Supranuclear Palsy, pallido-nigro-luysial atrophy variant of progressive supranuclear palsy, Other Tauopathy, Parkinson's Disease Dementia AD : Risk Modifier, FTD : Risk Modifier, DLB : Risk Modifier Extremely variable: Typically prominent tau pathology with variable involvement of Lewy bodies, amyloid plaques, or TDP-43 pathology. Reduced ability to bind microtubules; Less efficient microtubule assembly and impaired microtubule stability; More prone to tau oligomer formation and proteolysis by caspases.

rs143624519
Coding
Exon 7
Point, Missense
GCC to ACC
2 Kovacs et al., 2010;
Coppola et al., 2012
P176P
None FTD : Not Pathogenic Not applicable. Unknown.

rs1052551
Coding
Exon 7
Point, Silent
CCG to CCA
0 Rizzu et al., 1999
A178T
None FTD : Not Pathogenic Not applicable. Unknown.

rs63750612
Coding
Exon 7
Point, Missense
GCT to ACT
0 Houlden et al., 1999
G200E
None FTD : Not Pathogenic Not applicable. Unknown; predicted possibly damaging in silico.

rs757159453
Coding
Exon 6
Point, Missense
GGG to GAG
0 Sassi et al., 2014
P200P
None FTD : Not Pathogenic Not applicable. Unknown.

Coding
Exon 9
Point, Silent
CCC to CCT
0 Guerreiro et al., 2010
P202L
None FTD : Not Pathogenic Not applicable. Unknown.

rs63750417
Coding
Exon 4a
Point, Missense
CCG to CTG
0 Lilius et al., 1999
R211H
None FTD : Not Pathogenic Unknown. Unknown.

Coding
Exon 8
Point, Missense
CGC to CAC
0 Schulte et al., 2015
G213R
Alzheimer's Disease FTD : Not Pathogenic, AD : Unclear Pathogenicity Unknown. Unknown; predicted possibly damaging in silico.

rs76375268
Coding
Exon 4a
Point, Missense
GGG to AGG
0 Jin et al., 2012
V224G
Alzheimer's Disease, None FTD : Not Pathogenic, AD : Unclear Pathogenicity Unknown. Unknown; predicted possibly damaging in silico.

rs141120474
Coding
Exon 4a
Point, Missense
GTC to GGC
0 Jin et al., 2012
A227A
None FTD : Not Pathogenic Not applicable. Unknown. This variant segregates with the H2 haplotype, which may be associated with decreased tau levels in the brain.

rs1052553
Coding
Exon 9
Point, Silent
GCA to GCG
0 Rizzu et al., 1999
Q230R
Alzheimer's Disease, None FTD : Not Pathogenic, AD : Unclear Pathogenicity Not applicable. Unknown.

rs63750072
Coding
Exon 4a
Point, Missense
CAA to CGA
0 Rademakers et al., 2004
A239T
Frontotemporal Dementia FTD : Not Pathogenic Found in an individual with tau-negative microvacuolar-type neuropathology attributed to a GRN mutation. Unknown.

rs63750096
Coding
Exon 9
Point, Missense
GCC to ACC
0 Pickering-Brown et al., 2002
N255N
None FTD : Not Pathogenic Not applicable. Unknown.

rs17652121
Coding
Exon 9
Point, Silent
AAT to AAC
0 Poorkaj et al., 1998
K257T
Tauopathy consistent with Pick's Disease Other Tauopathy : Pathogenic, FTD : Unclear Pathogenicity Frontotemporal atrophy, especially in the temporal lobes. Numerous tau-positive Pick bodies in the neocortex, hippocampus, and some subcortical regions, which resembled those of sporadic Pick's disease. Diffuse hyperphosphorylated tau in some cell bodies. Recombinant tau protein with the K257T mutation showed reduced ability to promote microtubule assembly.

rs63750129
Coding
Exon 9
Point, Missense
AAG to ACG
0 Rizzini et al., 2000;
Pickering-Brown et al., 2000
I260V
Frontotemporal Dementia FTD : Pathogenic Extensive tau pathology, but no neurofibrillary tangles or Pick bodies. Mild macroscopic atrophy of the frontal lobes and dilatation of the anterior lateral ventricles, bilateral subdural hematomas. Neurodegeneration with gliosis, mild microvacuolation, and neuronal atrophy and loss in the frontal lobes. Selective increase in tau aggregation (four-repeat isoforms only); No disruption of exon 10 splicing.

rs63751249
Coding
Exon 9
Point, Missense
ATC to GTC
0 Grover et al., 2003
L266L
None FTD : Not Pathogenic Not applicable. Unknown.

Coding
Exon 9
Point, Silent
CTG to CTA
0 Guerreiro et al., 2010
L266V
Frontotemporal Dementia FTD : Pathogenic Severe atrophy of the frontal and temporal lobes; Extensive neuronal loss and gliosis; Many tau-positive inclusions, including Pick bodies; Tau-positive argyrophilic astrocytes with stout filaments and round or irregular argyrophilic inclusions. Increased levels of exon 10+ tau mRNA and soluble four-repeat (4R) tau; Decreased rate and extent of tau-induced microtubule assembly; A 3R isoform-specific increase in tau self-assembly.

rs63750349
Coding
Exon 9
Point, Missense
CTG to GTG
1 Kobayashi et al., 2003;
Hogg et al., 2003
P270P
None FTD : Not Pathogenic Not applicable. Unknown.

rs11568305
Coding
Exon 9
Point, Silent
CCG to CCA
0 Rizzu et al., 1999
G272V
Frontotemporal Dementia, Tauopathy consistent with Pick's Disease FTD : Pathogenic Severe frontotemporal lobe atrophy; Neuronal loss in hippocampus and caudate nucleus; "Ballooned cells" in cortex and basal ganglia; Tau-positive inclusions in multiple cortical and subcortical areas. Mutant tau proteins are more favorable substrates for phosphorylation than wild-type tau.

rs63750376
Coding
Exon 9
Point, Missense
GGC to GTC
2 Hutton et al., 1998
G273R
Frontotemporal Dementia FTD : Pathogenic Unknown. Unknown.

Coding
Exon 9
Point, Missense
GGG to AGG
0 van der Zee et al., 2006
N279K
Frontotemporal Dementia FTD : Pathogenic Widespread neuronal and glial tau accumulation in the cortex, basal ganglia, brain-stem nuclei, and white matter. Insoluble fraction is primarily 4R tau. Prominent tau deposition in the medial temporal cortices and upper and lower motor neurons with corticospinal tract degeneration. Affects splicing similar to many of the intronic mutations, resulting in more frequent inclusion of exon 10 in mRNA transcripts.

rs63750756
Coding
Exon 10
Point, Missense
AAT to AAG
0 Wszolek et al., 1992
K280del
Alzheimer's Disease, Frontotemporal Dementia, None, Tauopathy consistent with Pick's Disease FTD : Unclear Pathogenicity, AD : Unclear Pathogenicity Variable: Pick bodies comprised of 3R but not 4R tau and severe atrophy of the frontal and temporal cortices. Alternatively, tangles (Braak stage IV), neuritic amyloid plaques, extensive Lewy body pathology, moderate to severe atherosclerosis in brain vessles, and mild amyloid angiopathy.   The K280del variant is unusal in that it inhibits exon 10 inclusion and leads to an excess of 3-repeat (3R) tau transcripts. It also has been shown to reduce tau's ability to promote microtubule assembly.

rs63750688
Coding
Exon 10
Deletion
AAG to ---
2 Momeni et al., 2009;
Rizzu et al., 1999
L284L
Frontotemporal Dementia FTD : Pathogenic A variety of tau aggregates in both neurons and glia. In addition, a substantial number of diffuse and neuritic Aβ plaques, possibly due to coincident AD. The silent L284L increases transcripts containing exon 10 and decreases transcripts lacking exon 10. The mutation is thought to destroy an exon-splicing silencing element.

rs63751423
Coding
Exon 10
Point, Silent
CTT to CTC
0 D'Souza et al., 1999
L284R
Progressive Supranuclear Palsy Other Tauopathy : Pathogenic, FTD : Not Pathogenic Unknown. Unknown.

Coding
Exon 10
Point, Missense
CTT to CGT
0 Rohrer et al., 2011
D285D
None FTD : Not Pathogenic Not applicable. Unknown.

rs63750222
Coding
Exon 4a
Point, Silent
GAC to GAT
0 Poorkaj et al., 1998
D285N
Progressive Supranuclear Palsy, None FTD : Not Pathogenic, Other Tauopathy : Incomplete Penetrance Unknown. Unknown.

rs62063786
Coding
Exon 4a
Point, Missense
GAC to AAC
0 Poorkaj et al., 1998;
Higgins et al., 1999
S285R
Progressive Supranuclear Palsy FTD : Unclear Pathogenicity, PSP : Pathogenic Unknown. In vitro, this mutation affects exon 10 splicing, resulting in the overproduction of tau isoforms containing four microtubule binding repeat domains (4R tau).

Coding
Exon 10
Point, Missense
AGC to AGA
0 Ogaki et al., 2012
V287I
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Unknown.

rs149280278
Coding
Exon 10
Point, Missense
GTC to ATC
0 Jin et al., 2012
V289A
None FTD : Not Pathogenic Not applicable. Unknown.

rs62063787
Coding
Exon 4a
Point, Missense
GTA to GCA
0 Poorkaj et al., 1998
C291R
Apraxia of Speech, Corticobasal Syndrome Corticobasal Syndrome : Unclear Pathogenicity Unknown; MRI showed global atrophy of the cerebrum, especially in the left posterior frontal lobe. Unknown. In silico analysis predicted an increase in exon 10 splicing.

Coding
Exon 10
Point, Missense
TGT to CGT
0 Marshall et al., 2015
N296del
(ΔN296)
Progressive Supranuclear Palsy, Parkinson's Disease Other Tauopathy : Pathogenic Atrophy of the right precentral gyrus and the brainstem, as well as neuron loss and gliosis in the substantia nigra, several brainstem nuclei, and diencephalon. Hyperphosphorylated tau and neurofibrillary tangles in neurons in many brain regions. Accumulated tau in astrocytes and oligodendrocytes. The N296del mutation has little or no effect on exon 10 splicing, but substantially reduces tau's ability to promote microtubule assembly and increases its aggregation into filaments.

rs63751392
Coding
Exon 10
Deletion
AAT to ---
0 Pastor et al., 2001
N296D
Frontotemporal Dementia FTD : Pathogenic Unknown; imaging showed temporal atrophy. Unknown.

Coding
Exon 10
Point, Missense
AAT to GAT
0 Cohn-Hokke et al., 2014
N296H
Frontotemporal Dementia FTD : Pathogenic Localized frontotemporal lobe atrophy; A proliferation of tau-positive astrocytes; An accumulation of phosphorylated tau in both neurons and glia; An accumulation of four-repeat (4R) tau. This mutation increases the inclusion of exon 10 in tau mRNA and therefore increases the ratio of 4R/3R tau. It reduces tau's ability to promote tubulin polymerization and microtubule assembly. It has little to no effect on tau filament formation.

rs63750416
Coding
Exon 10
Point, Missense
AAT to CAT
0 Iseki et al., 2001
N296N
Frontotemporal Dementia, Progressive Supranuclear Palsy FTD : Pathogenic, PSP : Pathogenic Frontotemporal atrophy; Neuronal loss in the globus pallidus, substantia nigra, and locus ceruleus; Swollen achromatic neurons and tau-positive inclusions throughout the brain; Plaques and tangles were rare in the hippocampus and cerebral cortex. Increased inclusion of exon 10 in tau mRNA and thus increased the ratio of 4R/3R tau protein.

rs63750912
Coding
Exon 10
Point, Silent
AAT to AAC
0 Spillantini et al., 2000
A297V
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Unknown.

Coding
Exon 4a
Point, Missense
GCC to GTC
0 Jin et al., 2012
V300I
None FTD : Not Pathogenic Not applicable. Unknown; predicted benign and well-tolerated in silico.

Coding
Exon 10
Point, Missense
GTC to ATC
0 Guerreiro et al., 2010
P301L
Frontotemporal Dementia FTD : Pathogenic Tau aggregates consisting mainly of 4-repeat (4R) isoforms. Numerous intracytoplasmic tau deposits in neurons and glia in multiple brain regions, including the hippocampus, neocortex, and substantia nigra. Severe neuronal loss, gliosis, and a few ballooned cells in the frontal and temporal cortices. Strongly promotes β-sheet formation and accelerates the formation of paired helical filament; Does not affect exon 10 splicing.

rs63751273
Coding
Exon 10
Point, Missense
CCG to CTG
8 Hutton et al., 1998;
Dumanchin et al., 1998;
Clark et al., 1998;
Spillantini et al., 1998
P301P
Frontotemporal Dementia FTD : Not Pathogenic Patient had severe neuronal loss in the frontal and temporal cortices, globus pallidus, substantia nigra, red nucleus, and dentate nucleus. Tau-positive fibrillar structures in neurons and glia in these regions. The pathology was attributed to the IVS10+11 mutation in MAPT, which the patient also carried. No change in the ratio of 3-repeat (3R) to 4-repeat (4R) tau isoforms.

rs63751395
Coding
Exon 10
Point, Silent
CCG to CCA
0 Miyamoto et al., 2001
P301S
Frontotemporal Dementia FTD : Pathogenic Frontotemporal atrophy and extensive inclusions of hyperphosphorylated tau in neurons and glia. Recombinant tau protein with the P301S mutation showed a greatly impaired ability to promote microtubule assembly.

rs63751438
Coding
Exon 10
Point, Missense
CCG to TCG
4 Bugiani et al., 1999;
Sperfeld et al., 1999;
Lossos et al., 2003
P301T
Frontotemporal Dementia FTD : Pathogenic Mild global atrophy that was more prominent in the frontal and temporal lobes. Unknown.

rs63751438
Coding
Exon 10
Point, Missense
CCG to ACG
0 Lladó et al., 2007
G303V
Progressive Supranuclear Palsy Other Tauopathy : Pathogenic, FTD : Not Pathogenic Mild frontal and temporal atrophy with neuronal loss, gliosis, enlarged lateral ventricles, and microvacuolation. Accumulated tau in neurons and glia, including neurofibrillary tangles. Elevated 4-repeat (4R) isoforms.

Unknown.
 



rs63751391
Coding
Exon 10
Point, Missense
GGC to GTC
0 Ros et al., 2005
S305I
Argyrophilic Grain Disease FTD : Not Pathogenic, Other Tauopathy : Unclear Pathogenicity Extensive neuronal loss in the medial temporal cortex, hippocampus, and amygdala. No classical neurofibrillary tangles, Pick bodies, or neuritic plaques. Diffuse cytoplasmic tau in neurons, coiled bodies in oligodendrocytes, and argyrophilic grains. The tau-positive structures were composed only of 4-repeat (4R) isoforms. Affects exon 10 splicing, causing an overproduction of 4-repeat (4R) tau isoforms.

Coding
Exon 10
Point, Missense
AGT to ATT
0 Kovacs et al., 2008
S305N
Frontotemporal Dementia FTD : Pathogenic Numerous neurofibrillary tangles including some with an unusual, ring-shaped morphology around the nucleus, especially in the frontal, temporal, insular, and postcentral cortices, as well as in the dentate gyrus. Neurofibrillary tangles in neurons and glia. Stem-loop instability leading to alterations in the ratio of 3-repeat (3R) tau to 4-repeat (4R) tau.

rs63751165
Coding
Exon 10
Point, Missense
AGT to AAT
0 Iijima et al., 1999;
Kobayashi et al., 2002
S305S
Frontotemporal Dementia, Progressive Supranuclear Palsy FTD : Pathogenic, Other Tauopathy : Pathogenic Variable, but associated with cell loss, ballooned neurons, and tau-positive astrocytes, but limited cortical atrophy. Silver-positive neurofibrillary tangles associated with PSP diagnosis but not with FTDP-17 diagnosis. This silent mutation increases the splicing in of exon 10 and results in overproduction of tau isoforms containing four repeats (4R).

rs63750568
Coding
Exon 10
Point, Silent
AGT to AGC
0 Stanford et al., 2000;
Skoglund et al., 2008
L315L
Frontotemporal Dementia FTD : Pathogenic Unknown. Unknown.

rs63751231
Coding
Exon 11
Point, Silent
CTG to CTA
0
L315R
Frontotemporal Dementia, None FTD : Incomplete Penetrance Extensive tau pathology in neurons (Pick-like inclusions) and astrocytes, particularly in the frontotemporal cortex and hippocampus. Tau extracted from the cerebral cortex was present in straight and twisted tau filaments. Recombinant L315R tau protein has a compromised ability to promote microtubule assembly.

rs63749855
Coding
Exon 11
Point, Missense
CTG to CGG
0 van Herpen et al., 2003
K317M
Tauopathy with Parkinsonism and Motor Neuron Disease Other Tauopathy : Pathogenic Severe degeneration of the substantia nigra with extensive neuronal loss and gliosis. No Lewy bodies or Pick’s bodies. Severe neuron loss in the motor bulbar nuclei and anterior horn of the spinal cord. Frequent, diverse inclusions in oligodendrocytes and astrocytes. Phospho-tau-positive pre-tangles and tangles in neurons. Unknown.

rs63750092
Coding
Exon 11
Point, Missense
AAG to ATG
0 Zarranz et al., 2005
K317N
Globular Glial Tauopathy GGT : Pathogenic Lobar atrophy, especially in the inferior frontal gyrus. White-matter pathology, including vacuoles, gliosis, and loss of myelinated fibers. Extensive tau pathology, with tau-positive inclusions in neurons, astrocytes and oligodendrocytes. Distribution of tau pathology consistent with globular glial tauopathy, subtype III. Impaired tubulin polymerization. Altered tau aggregation in an isoform-specific manner; accelerated tau assembly in 4R tau while decreasing tau aggregation, misfolding, and filament assembly in 3R tau.

Coding
Exon 11
Point, Missense
AAG to AAC
0 Tacik et al., 2015
S318L
Alzheimer's Disease, None AD : Unclear Pathogenicity Unknown. Unknown.

rs73314997
Coding
Exon 4a
Point, Missense
TCG to TTG
0 Jin et al., 2012
S320F
Frontotemporal Dementia, Tauopathy consistent with Pick's Disease FTD : Pathogenic Neuropathology consistent with Pick's disease. Focal bilateral atrophy of the anterior temporal lobes with only very mild frontal atrophy; Severe neuronal loss and gliosis in the temporal cortex, cingulate gyrus, entorhinal cortex, and hippocampus. A marked reduction in the ability of tau to promote microtubule assembly; Removal of a potential phosphorylation site in tau.

rs63750635
Coding
Exon 11
Point, Missense
TCC to TTC
0 Rosso et al., 2002
S320Y
Tauopathy consistent with Pick's Disease Other Tauopathy : Pathogenic Unknown. Unknown.

Coding
Exon 11
Point, Missense
0
P332S
Frontotemporal Dementia FTD : Pathogenic Atrophy of primary motor and premotor cortices; neuronal tau-positive lesions mimicking Pick bodies, especially in the dentate gyrus, and containing aggregates of both 3-repeat (3R) and 4-repeat (4R) tau proteins. Reduced capacity to bind microtubules.

Coding
Exon 11
Point, Missense
CCA to TCA
0 Deramecourt et al., 2012
G335S
Frontotemporal Dementia FTD : Pathogenic Degeneration of the frontal and temporal lobes, hippocampus, and substantia nigra. Extensive deposition of tau, neurofibrillary tangles, and neuropil threads, but no Pick bodies. Tau-positive inclusions in neurons and glia. Sarkosyl-insoluble tau showed paired helical and straight filaments, and more irregular rope-like filaments. Reduced ability of tau to promote microtubule assemby.

rs63750095
Coding
Exon 12
Point, Missense
GGC to AGC
0 Spina et al., 2007
G335V
Frontotemporal Dementia FTD : Pathogenic Unknown. Reduced ability of tau to promote microtubule assembly; Increased heparin-induced assembly of recombinant tau into filaments.

rs63750905
Coding
Exon 12
Point, Missense
GGC to GTC
0 Neumann et al., 2005
Q336H
Pick's disease FTD : Pathogenic, Pick's disease : Pathogenic Neuropathology consistent with Pick's disease. Focal cortical atrophy and Pick bodies (cytoplasmic inclusions in neurons that were primarily negative for Gallyas silver stain). Pick bodies contained primarily 3R tau. Pick cells, called “swollen achromatic neurons” or “ballooned neurons,” were frequent in some brain regions. Increased rate and steady-state levels of microtubule polymerization; Greater tau filament assembly and aggregation, especially for 3R tau.  

Coding
Exon 12
Point, Missense
CAG to CAC
0 Tacik et al., 2015
Q336R
Frontotemporal Dementia, Pick's disease FTD : Pathogenic Atrophy of the frontal lobes, anterior temporal lobes, hippocampus, and amygdala. In some areas neuronal loss and astrogliosis were severe, leading to spongiosis. Hyperphosphorylated tau accumulated in swollen (Pick) cells. Intraneuronal inclusions (Pick bodies) containing both 3R and 4R tau and neurofibrillary tangle‐like structures. Increases tau fibrillogenesis. In contrast to most MAPT missense mutations, Q336R increases, rather than decreases, mutant tau's ability to promote microtubule assembly.

rs63750573
Coding
Exon 12
Point, Missense
CAG to CGG
0 Pickering-Brown et al., 2004
V337M
(Seattle)
Frontotemporal Dementia FTD : Pathogenic Neurofibrillary tangles comprised of paired helical filaments without plaques in several regions of the neocortex, amygdala, and parahippocampal gyrus. Accelerates aggregation of tau into filaments. The mutant protein also makes a more favorable substrate for phosphorylation than wild-type 4-repeat (4R) tau.

rs63750570
Coding
Exon 12
Point, Missense
GTG to ATG
3 Poorkaj et al., 1998;
Sumi et al., 1992
E342V
Frontotemporal Dementia FTD : Pathogenic Prominent frontotemporal neuron loss, cytoplasmic tau aggregates, paired helical tau filaments, increased 4-repeat (4R) tau mRNA, increased 4R tau without E2 or E3 inserts (4R0N), decreased 4R tau with these inserts (4R1N and 4R2N). Unknown.

rs63750711
Coding
Exon 12
Point, Missense
GAG to GTG
0 Lippa et al., 2000
S352L
Other Tauopathy Other Tauopathy : Pathogenic Extensive tau neuropathology. Recombinant S352L tau exhibited reduced microtubule binding and accelerated filament formation.

rs63750425
Coding
Exon 12
Point, Missense
TCG to TTG
0 Nicholl et al., 2003
S356T
Frontotemporal Dementia FTD : Pathogenic Frontotemporal and hippocampal atrophy. Some spongiosis. Abundant tau pathology (e.g., mature neurofibrillarly tangles and pretangles, tau-positive threads and grains). β-amyloid pathology largely absent. Unknown.

Coding
Exon 12
Point, Missense
TCC to ACC
0 Momeni et al., 2010
I360V
Parkinson's Disease PD : Unclear Pathogenicity Unknown. Unknown.

rs756903040
Coding
Exon 12
Point, Missense
ATC to GTC
0 Schulte et al., 2015
V363I
Frontotemporal Dementia FTD : Incomplete Penetrance Unknown; MRI showed massive brain atrophy. Unknown.

rs63750869
Coding
Exon 12
Point, Missense
GTC to ATC
0 Munoz et al., 2007;
Anfossi et al., 2011
P364S
Frontotemporal Dementia FTD : Pathogenic Neuronal loss and reactive gliosis in many regions, including the nucleus basalis of Meynert, substantia nigra, locus coeruleus, motor cortex, and the anterior horn of the spinal cord. Neuronal tau inclusions, especially globose neurofibrillary tangles with some flame-shaped neurofibrillary tangles. Some Pick body-like inclusions in one case. Reduced ability to promote microtubule assembly compared with wild-type tau and an increased rate of tau aggregation; Increased chromosomal instability and copy-number variations in lymphocytes and fibroblasts of mutation carriers.

Coding
Exon 12
Point, Missense
CCT to TCT
0 Rossi et al., 2012
G366R
Frontotemporal Dementia FTD : Pathogenic Unknown; MRI showed moderate to severe symmetrical cerebral atrophy predominantly involving the frontal lobe with ventricular enlargement. Reduced ability to promote microtubule assembly compared with wild-type tau, but similar aggregation kinetics; Increased chromosomal instability and copy number variations in lymphocytes and fibroblasts of mutation carriers.

Coding
Exon 12
Point, Missense
GGA to AGA
0 Rossi et al., 2012
K369I
Frontotemporal Dementia, Tauopathy consistent with Pick's Disease FTD : Pathogenic Brain atrophy, especially in the temporal lobes. Numerous tau-positive Pick bodies and Pick cells indistinguishable from those of sporadic Pick's disease in the neocortex, hippocampus, and subcortical brain regions. Recombinant tau proteins with the K369I mutation showed reduced ability to promote microtubule assembly.

rs63751264
Coding
Exon 12
Point, Missense
AAA to ATA
0 Neumann et al., 2001
R370W
None FTD : Not Pathogenic Not applicable. Unknown.

rs17651549
Coding
Exon 4a
Point, Missense
CGG to TGG
0 Lilius et al., 1999
E372G
Frontotemporal Dementia FTD : Pathogenic Tau-positive Pick body-like neuronal inclusions and swollen, tapering, thread-like processes in white matter. Atrophy of the frontal and temporal lobes, hippocampus, and amygdala. Gliosis, neuron loss in the hippocampus and substantia nigra, and corticospinal tract degeneration. Promotes tau filament formation and slightly decreases tau’s ability to promote microtubule assembly.

Coding
Exon 13
Point, Missense
GAA to GGA
0 Tacik et al., 2016
G389R
(G>C)
Frontotemporal Dementia FTD : Pathogenic Numerous neocortical tau-positive Pick body-like inclusions and filamentous axonal inclusions.   Recombinant G389R tau showed a reduced ability to promote microtubule assembly.

rs63750512
Coding
Exon 13
Point, Missense
GGG to CGG
0 Murrell et al., 1999;
Ghetti et al., 2000;
Rossi et al., 2008
G389R
(G>A)
Frontotemporal Dementia, Pick's disease FTD : Pathogenic, Other Tauopathy : Pathogenic Severe frontal lobe atrophy; neuronal loss; astrocytosis; tissue vacuolation. Recombinant G389R tau showed a reduced ability to promote microtubule assembly and an increased susceptibility to calpain I digestion.

rs63750512
Coding
Exon 13
Point, Missense
GGG to AGG
0 Pickering-Brown et al., 2000
R406W
Alzheimer's Disease, Frontotemporal Dementia FTD : Pathogenic Bilateral frontotemporal atrophy. Neuronal loss, gliosis, and abundant tau-positive inclusions, including neurofibrillary tangles. Generally sparse or absent Aβ plaques. Possible impairment in the ability to promote microtubule assembly.

rs63750424
Coding
Exon 13
Point, Missense
CGG to TGG
5 Hutton et al., 1998
L410F
Alzheimer's Disease AD : Not Pathogenic Not applicable. Unknown; predicted probably damaging in silico.

Coding
Exon 6
Point, Missense
CTT to TTT
0 Piccoli et al., 2016
N410H
CBD Other Tauopathy : Pathogenic Mild atrophy of the superior frontal cortex and enlargement of the lateral ventricles. Loss of neuromelanin in the midbrain. Abundant 4R tau-positive astrocytic plaques and numerous threads in the gray and white matter. Abundant ballooned neurons in the superior frontal cortex. Significant TDP-43 pathology, especially in the basal ganglia. Increase in the 4R/3R tau-mRNA ratio in patient brain. Recombinant tau with the N410H mutation had increased tau filament formation compared with wild-type tau, a decreased rate of microtubule assembly, and reduced overall microtubule polymerization.

Coding
Exon 13
Point, Missense
AAT to CAT
0 Kouri et al., 2014
S427F
Alzheimer's Disease, None, Parkinson's Disease Dementia PDD : Unclear Pathogenicity, AD : Unclear Pathogenicity Unknown. Unknown; predicted to be probably damaging in silico.

rs143956882
Coding
Exon 8
Point, Missense
TCC to TTC
0 Schulte et al., 2015
T427M
Frontotemporal Dementia, Parkinson's Disease FTD : Pathogenic, PD : Unclear Pathogenicity Unknown; MRI showed moderate frontotemporal atrophy. Unknown.

rs63750991
Coding
Exon 13
Point, Missense
ACG to ATG
0 Giaccone et al., 2005
H441Y
None FTD : Not Pathogenic Not applicable. Unknown.

rs2258689
Coding
Exon 6
Point, Missense
CAC to TAC
0 Poorkaj et al., 1998
S447P
None FTD : Not Pathogenic Not applicable. Unknown.

rs10445337
Coding
Exon 6
Point, Missense
TCC to CCC
0 Poorkaj et al., 1998
R448*
Parkinson's Disease PD : Unclear Pathogenicity Unknown. Unknown.

rs200099007
Coding
Exon 8
Point, Nonsense
CGA to TGA
0 Schulte et al., 2015
T504T
None FTD : Not Pathogenic Not applicable. Unknown.

rs62063845
Coding
Exon 8
Point, Silent
ACT to ACC
0 Higgins et al., 1999
P511R
None FTD : Not Pathogenic Not applicable. Unknown.

rs768343783
Coding
Exon 10
Point, Missense
CCA to CGA
0 Schulte et al., 2015
P512H
Alzheimer's Disease AD : Not Pathogenic Not applicable. Unknown; predicted probably damaging in silico.

rs192236920
Coding
Exon 8
Point, Missense
CCC to CAC
0 Piccoli et al., 2016
Duplication 17q21.31
Alzheimer's Disease Other Tauopathy : Pathogenic Neurofibrillary tangles in the hippocampus and entorhinal cortex. Aβ deposits were absent. The genomic duplication was associated with a 60-90% increase in the mRNA levels of MAPT.

Both
Duplicaton
0 Le Guennec et al., 2016
IVS9-10 G>T
(g(-10)t)
Frontotemporal Dementia FTD : Pathogenic Unknown. This intronic mutation stregthens the splice acceptor site, resulting in more frequent inclusion of exon 10 into mRNA transcripts.

rs63749974
Non-Coding
Intron 9
Point
G to T
0 Malkani et al., 2006
IVS9-15 T>C
Frontotemporal Dementia FTD : Unclear Pathogenicity Severe frontotemporal atrophy with relative sparing of the motor and visual cortices. Severe hippocampal pathology with neurons replaced by a dense band of astrocytic gliosis. Abundant tau pathology, primarily consisting of 3-repeat (3R) tau isoforms, consistent with Pick's disease. Ghost tangles in the cortex. When co-transfected with another splice-site variant, this mutation decreases the inclusion of exon 10, generating more E10- transcripts and resulting in an overproduction of 3-repeat (3R) tau isoforms.

Non-Coding
Intron 9
Point
T to C
0 Anfossi et al., 2011
IVS10+3 G>A
Frontotemporal Dementia FTD : Pathogenic Abundant filamentous tau deposits in the neocortex, some in subcortical nuclei, brainstem, and spinal cord. Deposits in neurons and glia, especially oligodendrocytes. Tau filaments are twisted and consist of 4-repeat (4R) tau isoforms. Destabilizes a stem-loop structure that regulates the alternative splicing of exon 10r, resulting in more frequent inclusion of exon 10 and an increased proportion of four-repeat (4R) tau isoforms..

rs63750013
Non-Coding
Intron 10
Point
G to A
0 Spillantini et al., 1998
IVS10+4 A>C
Frontotemporal Dementia FTD : Unclear Pathogenicity Severe frontotemporal atrophy with relative sparing of the motor and visual cortices. Severe hippocampal pathology with neurons replaced by a dense band of astrocytic gliosis. Abundant tau pathology, primarily consisting of 3-repeat (3R) tau isoforms, consistent with Pick's disease. Ghost tangles in the cortex. When co-transfected with another splice-site variant, decreases the inclusion of exon 10, resulting in an overproduction of 3-repeat (3R) tau isoforms.

Non-Coding
Intron 10
Point
A to C
0 Anfossi et al., 2011
IVS10+11 T>C
Frontotemporal Dementia FTD : Pathogenic Severe neuronal loss in the frontal and temporal cortices, globus pallidus, substantia nigra, red nucleus, and dentate nucleus. Tau-positive fibrillar structures in neurons and glia. Alters the splicing of exon 10, resulting in increased 4-repeat (4R) tau relative to 3-repeat (3R) tau.

rs63751394
Non-Coding
Intron 10
Point, Missense
T to C
0 Kowalska et al., 2002;
Miyamoto et al., 2001
IVS10+12 C>T
Frontotemporal Dementia FTD : Pathogenic Tau aggregates in neurons and glia; Isolated tau filaments with twisted, ribbon-like morphology comprised of hyperphosphorylated 4-repeat (4R) tau isoforms. Destabilizes a stem-loop structure that regulates the alternative splicing of exon 10, resulting in more frequent inclusion of exon 10 and an increased proportion of four-repeat (4R) tau isoforms.

rs63750916
Non-Coding
Intron 10
Point
C to T
0 Yasuda et al., 2000
IVS10+13 A>G
Frontotemporal Dementia FTD : Pathogenic Severe "knife‐edge" atrophy in the frontal and temporal lobes; Frequent neurofibrillary and glial tangles; Occasional ballooned neurons and damage to the substantia nigra. Destabilizes a stem-loop structure that regulates the alternative splicing of exon 10, resulting in more frequent inclusion of exon 10 and an increased proportion of four-repeat (4R) tau isoforms.

rs63750308
Non-Coding
Intron 10
Point
A to G
0 Hutton et al., 1998
IVS10+14 C>T
Frontotemporal Dementia FTD : Pathogenic Atrophy and spongiform changes in the frontotemporal cortex; Neuronal loss and gliosis in the substantia nigra and amygdala; Deposition of 4R tau. Destabilizes a stem-loop structure that regulates alternative splicing of exon 10, causing more frequent inclusion of exon 10 and leading to an increase in the proportion of four-repeat (4R) tau isoforms.

rs63750972
Non-Coding
Intron 10
Point
C to T
0 Hutton et al., 1998
IVS10+15 A>C
Frontotemporal Dementia FTD : Pathogenic Unknown; imaging showed bilateral anterior temporal lobe atrophy and hypometabolism. Destabilizes a stem-loop structure that regulates the alternative splicing of exon 10, resulting in more frequent inclusion of exon 10 and an increased proportion of four-repeat (4R) tau isoforms.

Non-Coding
Intron 10
Point
A to C
0 McCarthy et al., 2015
IVS10+16 C>T
Alzheimer's Disease, Frontotemporal Dementia, Progressive Supranuclear Palsy FTD : Pathogenic Neuronal loss, gray-matter gliosis, and neuropil vacuolation in both the frontal and temporal lobes. Balloon neurons in the cortex and degeneration of the substantia nigra with free melanin. Tau-positive neurons. Destabilizes a stem-loop structure that regulates the alternative splicing of exon 10, resulting in more frequent inclusion of exon 10 and an increased proportion of four-repeat (4R) tau isoforms.

rs63751011
Non-Coding
Intron 10
Point
C to T
1 Hutton et al., 1998
IVS10+19 C>G
Frontotemporal Dementia FTD : Pathogenic Frontal lobe atrophy; Frontal hypoperfusion. Alters the splicing of exon 10, resulting in increased 3-repeat (3R) tau isoforms. Elevated 3R tau was shown to decrease microtubule assembly.

rs63750162
Non-Coding
Intron 10
Point
C to G
0 Stanford et al., 2003
IVS10+25 C>T
None FTD : Not Pathogenic, AD : Not Pathogenic Not applicable. Unknown.

rs63750117
Non-Coding
Intron 10
Point
C to T
0 Roks et al., 1999
IVS10+29 G>A
None FTD : Not Pathogenic Not applicable. IVS10 + 29 G>A does not appear to alter the splicing of exon 10.

rs63751443
Non-Coding
Intron 10
Point
G to A
0 D'Souza et al., 1999;
Roks et al., 1999

PSEN1 (270)

PSEN1 encodes presenilin-1, a subunit of γ-secretase, the aspartyl protease responsible for Aβ generation. Over 180 mutations in PSEN1 have been reported and mutations in PSEN1 are the most common cause of early onset Alzheimer's disease.

Mutation Clinical
Phenotype
Pathogenicity Neuropathology Biological Effect Genomic Position Genomic Region Mutation Type
Codon Change
Research
Models
Primary
Papers
N32N
Alzheimer's Disease, None AD : Unclear Pathogenicity Unknown. Unknown.

Coding
Exon 4
Point, Silent
AAT to AAC
0 Scacchi et al., 2007
R35Q
Alzheimer's Disease, None AD : Not Pathogenic Not applicable. Unknown.

rs63750592
Coding
Exon 4
Point, Missense
CGG to CAG
0 Rogaeva et al., 2001
D40del (delGAC)
Alzheimer's Disease, Frontotemporal Dementia AD : Unclear Pathogenicity Unknown; MRI showed progressive cortical atrophy involving the lateral frontal lobes most prominently. Medial temporal lobe structures were also affected. Imaging by PET with florbetapir showed fibrillary Aβ deposits particularly in the frontal lobes. Unknown; predicted not pathogenic in silico and does not cause a frame-shift.

Coding
Exon 4
Deletion
GAC to ---
0 Nygaard et al., 2014
D40del (delACG)
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Unknown; does not cause a frame-shift.

Coding
Exon 4
Deletion
ACG to ---
0 Nicolas et al., 2015
E69D
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Unknown; predicted benign in silico.

Coding
Exon 4
Point, Missense
GAA to GAT
0 Nicolas et al., 2015
A79V
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD. Increased Aβ42/Aβ40 ratio; decreased Aβ40.

rs63749824
Coding
Exon 4
Point, Missense
GCC to GTC
0 Cruts et al., 1998
V82L
Alzheimer's Disease AD : Pathogenic Unknown. In CHO and HEK-293 cells expressing APP695, the mutant presenilin-1 resulted in a slightly lower ratio of secreted Aβ42/Aβ40.

rs63749967
Coding
Exon 4
Point, Missense
GTG to CTG
0 Campion et al., 1995
I83_M84del
(DelIM, ΔI83/M84, ΔI83/ΔM84)
Alzheimer's Disease, Spastic Paraparesis AD : Pathogenic Accumulation of noncongophilic, Aβ-positive, cotton-wool plaques in brain parenchyma. Widespread cerebral amyloid angiopathy, neurofibrillary tangles, and neuropil threads. Hexanucleotide deletion resulting in deletion of two amino acids (I and M). Cultured cells expressing mutant PSEN1 have an elevated Aβ42/Aβ40 ratio compared with cells transfected with wild-type PSEN1.

rs63750307
Coding
Exon 4
Deletion
ATC.ATG to ---.---
0 Houlden et al., 2000;
Steiner et al., 2001
I83T
Alzheimer's Disease AD : Pathogenic Unknown; MRI showed bilateral atrophy, especially in the parietal and temporal lobes. Unknown; predicted probably damaging in silico.

Coding
Exon 4
Point, Missense
ATC to ACC
0 Achouri-Rassas et al., 2015
M84V
Alzheimer's Disease, Spastic Paraparesis AD : Pathogenic Neuropathology consistent with AD in 2 cases. MRI showed cortical and cerebellar atrophy in 2 cases; frontal and temporal lobe atrophy in a third case. Increased Aβ42 and Aβ42/Aβ40 ratio in cells; predicted to be possibly damaging by PolyPhen and to be disease-causing by MutationTaster.

Coding
Exon 4
Point, Missense
ATG to GTG
0 Hooli et al., 2014
L85P
Alzheimer's Disease, Spastic Paraparesis AD : Pathogenic Neuropathological examination was not available. SPECT and PET showed bilateral hypoperfusion and hypometabolism in the occipital and temporal lobes. Increased Aβ42/Aβ40 ratio; increased Aβ42.

rs63750599
Coding
Exon 4
Point, Missense
CTC to CCC
0 Ataka et al., 2004
P88L
Alzheimer's Disease AD : Pathogenic Unknown, but MRI showed generalized cortical atrophy. Increased ratio of Aβ42,43/Aβ40 and generation of Aβ45 and Aβ46.

Coding
Exon 4
Point, Missense
CCT to CTT
0 Liu et al., 2017
V89L (G>T)
Alzheimer's Disease AD : Pathogenic Neurofibrillary tangles and neuritic plaques with dystrophic neurites corresponding to stage VI of Braak and Braak. Plaques abundant in the hippocampus, amygdala, and neocortex. Tangles abundant in the neocortex and hippocampus. Some amyloid angiopathy in cortical vessels. Moderate cortical atrophy and enlarged ventricles. Unknown.

rs63750815
Coding
Exon 4
Point, Missense
GTG to TTG
0 Queralt et al., 2002
V89L (G>C)
Alzheimer's Disease AD : Pathogenic Typical Alzheimer's disease pathology. Unknown, but predicted to be deleterious by SIFT and probably damaging by PolyPhen-2.

Coding
Exon 4
Point, Missense
GTG to CTG
0 Liu et al., 2017
C92S
Alzheimer's Disease AD : Pathogenic Unknown. Increases Aβ42 secretion from mammalian cells and from fibroblasts cultured from a mutation carrier. Elevated Aβ42/Aβ40 ratio.

rs63751141
Coding
Exon 4
Point, Missense
TGC to TCC
0 Tedde et al., 2003
V94M
Alzheimer's Disease AD : Pathogenic Unknown. Unknown.

rs63750831
Coding
Exon 4
Point, Missense
GTG to ATG
0 Arango et al., 2001
V96F
Alzheimer's Disease AD : Pathogenic Unknown. Unknown.

rs63750601
Coding
Exon 4
Point, Missense
GTC to TTC
0 Kamino et al., 1996
V97L
Alzheimer's Disease AD : Pathogenic Unknown; MRI from two mutation carriers showed enlarged lateral ventricles and atrophy of the cerebral cortex, especially the temporal lobes. Elevated intracellular and extracellular Aβ42 compared to mock-transfected cells and those expressing wild-type PSEN1.

rs63750852
Coding
Exon 4
Point, Missense
GTG to TTG
0 Jia et al., 2005
T99A
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Unknown.

Coding
Exon 4
Point, Missense
ACC to GCC
0 Ikeda et al., 2013
F105C
Alzheimer's Disease AD : Pathogenic Unknown; neuroimaging showed enlarged ventricles and atrophy in the hippocampus and frontotemporal regions. Unknown; predicted damaging in silico.

Coding
Exon 4
Point, Missense
TTT to TGT
0 Jiao et al., 2014;
Deng et al., 2014
F105I
Alzheimer's Disease AD : Pathogenic Unknown. Unknown.

rs63750325
Coding
Exon 4
Point, Missense
TTT to ATT
0 Raux et al., 2005
F105L
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD, including numerous neurofibrillary tangles and senile plaques in the hippocampus with scattered plaques in the cortex. Unknown.

rs63750321
Coding
Exon 4
Point, Missense
TTT to TTG
0 Finckh et al., 2000
F105V
Alzheimer's Disease AD : Pathogenic Unknown. Unknown; predicted probably damaging in silico.

Coding
Exon 4
Point, Missense
TTT to GTT
0 Gómez-Tortosa et al., 2010
R108Q
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Unknown.

rs200646139
Coding
Exon 4
Point, Missense
CGG to CAG
0 Dobricic et al., 2012
L113_I114insT
(Intron4, InsTAC, p.113+1delG, splice5)
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD, including neuron loss in the hippocampus and entorhinal cortex, neuritic plaques and neurofibrillary tangles in the hippocampus, and amyloid angiopathy, particularly evident in the cerebellum. Deletion of a G in splice donor site of intron 4 produces three aberrant transcripts. Increased Aβ42 and Aβ42/Aβ40; reduced Aβ40 and Aβ38 production in patient brain membranes. In iPSC-derived neurons, increased Aβ42/Aβ40, Aβ42/Aβ38, and Aβ43/Aβ40 ratios, while decreased Aβ38/Aβ40. Also, increased BACE1–BACE2 products (Aβ19/20) and BACE1–BACE1/BACE2 products (Aβ34).

rs63751475
Both
Intron 4
Insertion/Deletion
G to -
0 Tysoe et al., 1998;
De Jonghe et al., 1999
L113P
Frontotemporal Dementia FTD : Pathogenic, Possible AD : Pathogenic AD-like plaques and tangles; CT scans showed predominant frontotemporal atrophy and SPECT showed hypoperfusion including the frontal lobes. Unknown.

rs63751399
Coding
Exon 4
Point, Missense
CTA to CCA
0 Raux et al., 2000
L113Q
Alzheimer's Disease AD : Pathogenic Neuritic plaques (Braak stage C); Neurofibrillary tangles (stage VI); Severe amyloid angiopathy. Unknown.

rs63751399
Coding
Exon 4
Point, Missense
CTA to CAA
0 Finckh et al., 2005
Y115C
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD. HEK-293 cells transfected with mutant PSEN1 secreted significantly more Aβ42 (approximately 5.4-fold) than cells expressing wild-type PSEN1. The Aβ42:Aβ40 ratio was also increased.

rs63750450
Coding
Exon 5
Point, Missense
TAT to TGT
0 Cruts et al., 1998
Y115D
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD. Unknown.

rs63749962
Coding
Exon 5
Point, Missense
TAT to GAT
0
Y115H
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD. Increased Aβ42/Aβ40, Aβ42/Aβ38, and Aβ43/Aβ40 ratios, while leaving Aβ38/Aβ40 unchanged, in iPSCs. Reduced production of Aβ40 and Aβ38 in vitro; decreased intracelluar Aβ40. Suppressed Aβ production by wild-type PSEN1.    

rs63749962
Coding
Exon 5
Point, Missense
TAT to CAT
0 Campion et al., 1995
T116I
Alzheimer's Disease AD : Pathogenic Unknown. Unknown.

rs63750730
Coding
Exon 5
Point, Missense
ACC to ATC
0 La Bella et al., 2004
T116N
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD. Unknown.

rs63750730
Coding
Exon 5
Point, Missense
ACC to AAC
0 Romero et al., 1999
T116R
Alzheimer's Disease AD : Pathogenic Unknown. Unknown.

Coding
Exon 5
Point, Missense
0 Mann et al., 2001
P117A
Alzheimer's Disease, Ataxia AD : Pathogenic Unknown. Unchanged total Aβ levels; increased Aβ42/Aβ total ratio.

Coding
Exon 5
Point, Missense
CCA to GCA
0 Anheim et al., 2007
P117L
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD. Unusually high amyloid burden, especially in the molecular layer of the cerebellum and in cerebellar vessels. In vitro, mutant PSEN1 increases Aβ42, inhibits neurite outgrowth and neurofilament assembly, increases cell-cycle arrest, and decreases neuronal differentiation of progenitor cells.

rs63749805
Coding
Exon 5
Point, Missense
CCA to CTA
1 Wisniewski et al., 1998
P117R
Alzheimer's Disease AD : Pathogenic Unknown. Increased Aβ42/Aβ40 ratio; increased Aβ42; increased Aβ40; Affects on cell cycle in immortalized patient lymphocytes.

rs63749805
Coding
Exon 5
Point, Missense
CCA to CGA
0 Zekanowski et al., 2003
P117S
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD according to CERAD criteria; Neuronal loss estimated to be greater than 70 percent in one brain; extensive loss of white matter; active gliosis throughout the brain; Lewy bodies. Unchanged total Aβ; Increased relative secretion of Aβ42 by N2a cells and skin fibroblasts from a mutation carrier; Reduced neurite outgrowth in N2a cells compared to cells expressing wild-type PSEN1.

rs63750550
Coding
Exon 5
Point, Missense
CCA to TCA
0 Dowjat et al., 2004
E120D (A>C)
Alzheimer's Disease AD : Pathogenic Unknown. Unknown.

rs63751272
Coding
Exon 5
Point, Missense
GAA to GAC
0 Poorkaj et al., 1998
E120D (A>T)
Alzheimer's Disease AD : Pathogenic Unknown. Unknown.

rs63751272
Coding
Exon 5
Point, Missense
GAA to GAT
0 Reznik-Wolf et al., 1996
E120G
Alzheimer's Disease AD : Pathogenic

Frequent amyloid plaques and neurofibrillary tangles; Severe amyloid angiopathy.
 

Unknown; predicted probably damaging in silico.

Coding
Exon 5
Point, Missense
GAA to GGA
0 Lladó et al., 2009;
Gómez-Tortosa et al., 2010
E120K
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD. Increased Aβ42/Aβ total ratio in cell lines.

rs63750800
Coding
Exon 5
Point, Missense
GAA to AAA
0 Hutton et al., 1996
E123K
Alzheimer's Disease AD : Pathogenic

rs63750378
Coding
Exon 5
Point, Missense
GAG to AAG
0 Yasuda et al., 1999
Q127_R128del(CAGA);InsG(G)
(c.379_382delXXXXinsG)
Alzheimer's Disease AD : Unclear Pathogenicity Unknown In cells, no effect on Aβ40 and Aβ42 levels. SIFT predicts mutation is tolerated. 

Coding
Exon 5
Insertion/Deletion
CAGAGA to GGA
0 Hsu et al., 2018
H131R
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Unknown.

Coding
Exon 5
Point, Missense
CAC to CGC
0 Ikeda et al., 2013
S132A
Dementia with Lewy Bodies DLB : Pathogenic, AD : Pathogenic Neuropathology consistent with AD, with severe neocortical Lewy body disease (one case). Unknown

rs200937800
Coding
Exon 5
Point, Missense
TCA to GCA
0 Ryan et al., 2016
L134R
Alzheimer's Disease AD : Pathogenic Unknown; MRI of the Turkish proband showed atrophy of the cerebrum and cerebellum. Unknown; predicted probably damaging in silico.

Coding
Exon 5
Point, Missense
CTG to CGG
0 Lohmann et al., 2012
N135D
Alzheimer's Disease AD : Pathogenic Brain biopsy showed mild loss of neurons and secondary gliosis with multiple neuritic plaques and abundant neurofibrillary tangles. Increased Aβ42/Aβ40 ratio in cell lines; increases intracellular and secreted Aβ42 and decreases Aβ40.

rs63750353
Coding
Exon 5
Point, Missense
AAT to GAT
0 Crook et al., 1997
N135S
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD, including widespread neurofibrillary tangles and neuritic plaques. Some cotton-wool plaques; Mild amyloid angiopathy; Corticospinal tract pathology. Unknown.

rs63751278
Coding
Exon 5
Point, Missense
AAT to AGT
0 Finckh et al., 2005
N135Y
Alzheimer's Disease AD : Pathogenic Postmortem findings consistent with AD. Reduced levels of secreted Aβ40 and higher Aβ42/Aβ40 ratio.

Coding
Exon 5
Point, Missense
AAT to TAT
0 Natelson Love et al., 2017
A136G
Alzheimer's Disease AD : Pathogenic In vitro assays showed a moderate decrease in both Aβ40 and Aβ42 production, with the Aβ42/Aβ40 ratio remaining roughly similar to wildtype. Neuroblastoma cells carrying the mutation showed enhanced sensitivity to trophic withdrawal. Also, the mutation enhanced PSEN1 cleavage of ER calcium sensor STIM1, resulting in dendritic spine disruption. Polyphen analysis predicted probably damaging; SIFT predicted tolerated. 

rs41345849
Coding
Exon 5
Point, Missense
GCT to GGT
0 Xu et al., 2002
M139I (G>C)
Alzheimer's Disease AD : Pathogenic Possible mislocalization of presenilin-1 protein; co-localization with tangles. Increased Aβ42/Aβ total ratio.

rs63750522
Coding
Exon 5
Point, Missense
ATG to ATC
0 Kim et al., 2010
M139I (G>A)
Alzheimer's Disease AD : Pathogenic Possible mislocalization of presenilin-1 protein; co-localization with tangles. Increased Aβ42/Aβ total ratio.

rs63750522
Coding
Exon 5
Point, Missense
ATG to ATA
0 Boteva et al., 1996
M139K
Alzheimer's Disease AD : Pathogenic Unknown. Unknown.

rs63751106
Coding
Exon 5
Point, Missense
ATG to AAG
0 Dumanchin et al., 1998
M139L
Alzheimer's Disease AD : Pathogenic Unknown, but MRI in two individuals revealed bilateral atrophy in the hippocampus and cerebral cortex.  Aβ40 levels moderately decreased; Aβ42/Aβ40 ratio increased in cultured cells.

Coding
Exon 5
Point, Missense
ATG to TTG
0 Qiu et al., 2019
M139T
Alzheimer's Disease AD : Pathogenic Unknown. Increased Aβ42/Aβ total ratio.

rs63751106
Coding
Exon 5
Point, Missense
ATG to ACG
0 Campion et al., 1995
M139V
Alzheimer's Disease, Atypical Dementia AD : Pathogenic Neuropathology consistent with AD. Increased Aβ42/Aβ40, Aβ42/Aβ38, Aβ43/Aβ40, and Aβ2-40:Aβ40; decreased Aβ38/Aβ40, Aβ38/Aβ42, Aβ40/Aβ43, and Aβ11-40:Aβ40. Decreases Aβ40 and Aβ38 levels, while increasing Aβ42 and Aβ43 levels. Mutant protein levels were variable in iPSC-derived neurons suggesting protein instability.    

rs63751037
Coding
Exon 5
Point, Missense
ATG to GTG
0 , 1995
V142F
Alzheimer's Disease AD : Pathogenic Unknown, but MRI showed severe cortical atrophy that was most pronounced in frontal and temporal lobes. Predicted to be pathogenic by MutPred, SNPs&Go, MutationTaster, and SIFT.

Coding
Exon 5
Point, Missense
GTC to TTC
0 Wang et al., 2018
I143F
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD, but in one case, more widespread distribution of plaques in the temporal sulcus compared with sporadic AD, and lower ratio of Ab40 to Ab42/Ab43 in plaques. Also, accelerated NFT formation and neuronal loss. Unknown. Conservative amino acid substitution in a putative transmembrane domain.

rs63750322
Coding
Exon 5
Point, Missense
ATT to TTT
0 Rossor et al., 1996;
Palmer et al., 1999
I143M
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD in one case. Unknown

rs63751071
Coding
Exon 5
Point, Missense
ATT to ATG
0 Heckmann et al., 2002
I143N
Alzheimer's Disease AD : Pathogenic Unknown Unknown

rs63750004
Coding
Exon 5
Point, Missense
ATT to AAT
0 Raux et al., 2005
I143T
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD. Increased Aβ42/Aβ40 ratio; increased Aβ42; decreased Aβ40.

rs63750004
Coding
Exon 5
Point, Missense
ATT to ACT
0 Cruts et al., 1995;
Rogaeva et al., 2001
I143V
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD, including abundant amyloid plaques and severe neurofibrillary tangle pathology (stage VI Braak and Braak). Amyloid deposits were comprised largely of Aβ42, with little to no Aβ40. There was minimal amyloid angiopathy in vessels. Increased Aβ42.

Coding
Exon 5
Point, Missense
ATT to GTT
0 Gallo et al., 2011
M146I (G>C)
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD in 3 cases, but more involvement of central grey areas, no vascular lesions, and very mild amyloid angiopathy. Increased Aβ42/Aβ40 and Aβ42/Aβ38; unchanged Aβ38/Aβ40 and Aβ43/Aβ40 in iPSC-derived neurons, suggesting inefficient carboxypeptidase activity. Variability in mutant protein levels, consistent with altered protein stability.

rs63750391
Coding
Exon 5
Point, Missense
ATG to ATC
0 Gustafson et al., 1998
M146I (G>T)
Alzheimer's Disease AD : Pathogenic Unknown Increased Aβ42/Aβ40 and Aβ42/Aβ38; unchanged Aβ38/Aβ40 and Aβ43/Aβ40 in iPSC-derived neurons, suggesting inefficient carboxypeptidase activity. High degree of variablilty in mutant protein levels, consistent with altered protein stability. 

rs63750391
Coding
Exon 5
Point, Missense
ATG to ATT
0 Rogaeva et al., 2001
M146I (G>A)
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD. Increased Aβ42/Aβ40 and Aβ42/Aβ38; unchanged Aβ38/Aβ40 and Aβ43/Aβ40 in iPSC-derived neurons, suggesting inefficient carboxypeptidase activity.Variable protein levels, consistent with altered protein stability.

rs63750391
Coding
Exon 5
Point, Missense
ATG to ATA
0 Jørgensen et al., 1996;
Raja et al., 2016;
Jakobsen et al., 2016
M146L (A>C)
Alzheimer's Disease, Pick's disease AD : Pathogenic Neuropathology consistent with AD in multiple affected mutation carriers. Pick bodies also have been noted in some cases. Increased Aβ42/Aβ total ratio; increased Aβ42/Aβ40 ratio; increased Aβ42. No change in Aβ38 or Aβ40 levels. Disrupts calcium dynamics and mitochondrial permeability.

rs63750306
Coding
Exon 5
Point, Missense
ATG to CTG
13 Sherrington et al., 1995;
Sorbi et al., 1995;
, 1995
M146L (A>T)
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD. Increased Aβ42, Aβ42/Aβ total, Aβ42:Aβ40 in cells and in vitro assays. No significant change in Aβ38 or Aβ40. Impaired calcium dynamics and mitochondrial permeability.

rs63750306
Coding
Exon 5
Point, Missense
ATG to TTG
0 Mangone et al., 1995;
Morelli et al., 1998
M146V
Alzheimer's Disease, Frontotemporal Dementia AD : Pathogenic, FTD : Unclear Pathogenicity Variable: Neuropathology consistent with AD in some cases, but also, in at least one case, mixed pathology including frequent Aβ deposits, tangles, and Pick bodies. Increased Aβ42/Aβ40 ratio; increased Aβ42; lowers wild-type PSEN1 gene expression. Inhibits store-operated calcium channel activity, associated with loss of dendritic spines. Increases calcineurin activity, impairs trafficking of glutamate AMPA receptors.

rs63750306
Coding
Exon 5
Point, Missense
ATG to GTG
6 , 1995
T147I
Alzheimer's Disease AD : Pathogenic Unknown. Unknown; predicted probably damaging in silico.

rs63750907
Coding
Exon 5
Point, Missense
ACT to ATT
0 Campion et al., 1999
T147P
Alzheimer's Disease, Ataxia AD : Pathogenic Unknown; neuroimaging showed widespread cortical atrophy, as well as atrophy in the medial temporal lobes, with less severe cerebellar atrophy. Unknown; predicted probably damaging in silico.

Coding
Exon 5
Point, Missense
ACT to CCT
0 Testi et al., 2014
L150P
Alzheimer's Disease AD : Pathogenic Unknown. Unknown.

Coding
Exon 6
Point, Missense
CTG to CCG
0 Wallon et al., 2012
L153V
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD in one case.  Decreased Aβ40 and Aβ42 production in vitro.

rs63751441
Coding
Exon 5
Point, Missense
CTG to GTG
0 Raux et al., 2000;
Janssen et al., 2001
Y154C
Alzheimer's Disease AD : Pathogenic Unknown Unknown

rs63751292
Coding
Exon 5
Point, Missense
TAT to TGT
0 Janssen et al., 2003
Y154N
Alzheimer's Disease, Spastic Paraparesis AD : Pathogenic Unknown, MRI and SPECT showed atrophy and hypoperfusion in occipito-parietal areas and internal temporal lobe areas, including the hippocampus. Decreased Aβ42 in CSF. Dramatically decreased Aβ40 and Aβ42 production in vitro.

rs63750588
Coding
Exon 5
Point, Missense
TAT to AAT
0 Hattori et al., 2004
Y156F; Y156_R157insIY
Alzheimer's Disease, Spastic Paraparesis AD : Pathogenic Neuropathology in one case was consistent with AD, but more widespread and included cotton-wool plaques. FDG-PET in 2 individuals showed hypometabolism starting in posterior temporo-parietal cortex and spreading rapidly to posterior cingulate, primary motor, and frontal association cortices.  Unknown

rs63750631
Coding
Exon 5
Insertion
TAC to TTT.ATA.TAC
0 Rogaeva et al., 2001;
Moretti et al., 2004
R157S
Alzheimer's Disease AD : Unclear Pathogenicity Unknown In silico analyses predicted the mutation is likely pathogenic: Polyphen 2, probably damaging; SIFT, deleterious; CADD score, 31.

rs201617677
Coding
Exon 5
Point, Missense
AGG to AGT
0 Jiang et al., 2019
H163P
Alzheimer's Disease AD : Unclear Pathogenicity Brain biopsy of the frontal cortex showed numerous senile plaques and neurofibrillary tangles compatible with a diagnosis of AD. No spongiform changes or abnormal prion proteins were detected. Increased Aβ42/Aβ40 ratio; increased Aβ42; decreased Aβ40.

Coding
Exon 5
Point, Missense
CAT to CCT
0 Kim et al., 2012
H163R
Alzheimer's Disease, Myoclonus AD : Pathogenic Data are limited, but neuropathology consistent with AD has been observed in at least one case. Increased Aβ42/Aβ total ratio in COS-1 cells; drastic reduction of Aβ42 and Aβ40 production in vitro. Affects γ-secretase-dependent neurexin processing.

rs63750590
Coding
Exon 5
Point, Missense
CAT to CGT
1 Campion et al., 1995;
Sherrington et al., 1995;
Tanahashi et al., 1995
H163Y
Alzheimer's Disease AD : Pathogenic Typical AD neuropathology (one case); decreased glucose metabolism in presymptomatic mutation carriers, especially in the thalamus. Widespread brain amyloid (PiB-PET) and shrunken hippocampi. Decreased CSF Aβ42 and Aβ38 levels. Increased Aβ42/Aβ total ratio when expressed in COS-1 cells co-transfected with APP695, and increased Aβ42 production in an in vitro assay using purified proteins.

rs63749885
Coding
Exon 5
Point, Missense
CAT to TAT
0 , 1995
A164V
Alzheimer's Disease AD : Pathogenic Unknown; MRI showed generalized atrophy of the brain with pronounced involvement of the anterior temporal lobe, including the hippocampus. Unknown; predicted possibly damaging in silico.

Coding
Exon 6
Point, Missense
GCC to GTC
0 Roeber et al., 2015
W165C (G>C)
Alzheimer's Disease AD : Pathogenic Unknown Increased Aβ42 and decreased Aβ40 production in vitro; elevated Aβ42/Aβ40 ratio (W165C mutant with unspecified nucleotide change).

rs63741484
Coding
Exon 6
Point, Missense
TGG to TGC
0 Campion et al., 1999
W165C (G>T)
Alzheimer's Disease AD : Pathogenic Unknown, MRI showed diffuse cerebral and cerebellar atrophy in one case. Increased Aβ42 and decreased Aβ40 production in vitro; elevated Aβ42/Aβ40 ratio (W165C mutant with unspecified nucleotide change). Also, SIFT and polyphen programs predict mutation is deleterious, probably damaging.

Coding
Exon 6
Point, Missense
TGG to TGT
0 Syama et al., 2018
W165G
Alzheimer's Disease AD : Pathogenic Unknown; but SPECT showed slight decrease in blood flow to parieto-occipital regions and thalamus in one case. Also, EEG alterations, but normal MRI. In vitro, increased Aβ42 and Aβ42/Aβ40 ratio; reduced Aβ40.

rs63751010
Coding
Exon 6
Point, Missense
TGG to GGG
0 Higuchi et al., 2000
L166H
Alzheimer's Disease AD : Pathogenic Unknown; MRI showed marked hippocampal atrophy and cortical atrophy, especially in the insula and the peri-insular temporal lobe. SPECT imaging showed bilateral hypometabolism in the parietal and frontal lobes. Unknown.

rs63750265
Coding
Exon 6
Point, Missense
CTT to CAT
0 Pantieri et al., 2005
L166P
Alzheimer's Disease, Spastic Paraparesis AD : Pathogenic In one individual, numerous Aβ-positive neuritic and cotton-wool plaques throughout the cerebral cortex; abundant Aβ-positive amyloid cores in the cerebellar cortex. In another, robust amyloid pathology in the striatum and cerebellum, and asymmetric tau pathology in the primary sensorimotor cortex contralateral to the side most affected by spasticity. Increased Aβ42/Aβ ratio; reduced Aβ40, Aβ42, and AICD. Reduced cleavage of Notch and N-cadherin. Also, dominant-negative effect on wild-type PSEN1, and inhibition of calcium leak channel in the ER.

rs63750265
Coding
Exon 6
Point, Missense
CTT to CCT
4 Moehlmann et al., 2002
L166R
Alzheimer's Disease AD : Pathogenic Unknown; MRI in the proband showed cortical atrophy; PET showed parietal hypoperfusion. Unknown.

rs63750265
Coding
Exon 6
Point, Missense
CTT to CGT
0 Ezquerra et al., 2000
L166V
Alzheimer's Disease AD : Pathogenic SPECT imaging performed four years after symptom onset showed temporoparietal hypoperfusion. Postmortem evaluation revealed neuropathology consistent with AD, including advanced plaques and tangles (CERAD C, Braak stage VI). Unknown; predicted possibly damaging in silico.

Coding
Exon 6
Point, Missense
CTT to GTT
0 Sassi et al., 2014
L166del
Alzheimer's Disease AD : Pathogenic Unknown; MRI showed generalized, symmetrical cerebral atrophy, which was most prominent in the medial temporal lobes. Unknown.

rs63751458
Coding
Exon 6
Deletion
CTT to ---
0 Knight et al., 2007
I167del (TTAdel)
Alzheimer's Disease AD : Pathogenic Unknown. Unknown; predicted pathogenic in silico.

Coding
Exon 6
Deletion
TTA to ---
0 Jiao et al., 2014
I167del (TATdel)
Alzheimer's Disease AD : Pathogenic Unknown This mutation involves a trinucleotide deletion resulting in the in-frame deletion of one amino acid (I).

rs63750879
Coding
Exon 6
Deletion
ATT.ATA to ATA
0 Janssen et al., 2003
I168T
Alzheimer's Disease AD : Unclear Pathogenicity Neuropathology consistent with AD. Unknown; predicted possibly damaging in silico.

Coding
Exon 6
Point, Missense
ATA to ACA
0 Sassi et al., 2014
S169del
(ΔS169, Ser169del, ΔS170)
Alzheimer's Disease AD : Pathogenic Unknown; MRI of the proband showed generalized cerebral atrophy with enlargement of the ventricles and widening of the sulci. Unknown.

Coding
Exon 6
Deletion
TCA.TCT to ---.TCT
0 Guo et al., 2010
S169L
Alzheimer's Disease AD : Pathogenic Neuropathology typical of AD, but also Aβ deposition in the cerebellum and white matter, as well as numerous ectopic neurons, often containing tau-immunopositive neurofibrillary tangles, in the white matter of the frontal and temporal lobes, possibly due to errant migration during development. Unknown.

rs63751210
Coding
Exon 6
Point, Missense
TCA to TTA
0 Taddei et al., 1998
S169P
Alzheimer's Disease, Myoclonic seizure AD : Pathogenic Neuropathology consistent with AD, including numerous plaques and neurofibrillary tangles, neuritic irregularities, neuronal lipofuscin, and mild astrocytosis. Unknown.

rs63750418
Coding
Exon 6
Point, Missense
TCA to CCA
0 Ezquerra et al., 1999
S170F
Alzheimer's Disease AD : Pathogenic Variable: Some cases with typical AD pathology; Extensive Lewy bodies in the substantia nigra and throughout the brain have also been reported. One case had severe cerebellar pathology, including abundant amyloid deposition and loss of Purkinje cells. Variable: May increase both Aβ42 and Aβ40 or just Aβ42, altering the ratio.

rs63750577
Coding
Exon 6
Point, Missense
TCT to TTT
0 Snider et al., 2005
S170P
Alzheimer's Disease AD : Pathogenic, Parkinsonism : Pathogenic In AD case, typical AD tau pathology was reported. In parkinsonism case, MRI revealed hypointensity in the putamen, globus pallidus, and substantia nigra, as well as frontotemporal cortical atrophy. SPECT showed severe nigrostriatal dopaminergic deficit bilaterally, and 18F-FDG PET hypometabolism in striatal and posterior cingulate. Predicted damaging by Poly-Phen-2 and Mutation Taster

rs63750577
Coding
Exon 6
Point, Missense
TCT to CCT
0 Irwin et al., 2013;
Carecchio et al., 2017
L171P
Alzheimer's Disease AD : Pathogenic

rs63750963
Coding
Exon 6
Point, Missense
CTA to CCA
0 Ramirez-Dueñas et al., 1998
L173F (G>C)
Alzheimer's Disease AD : Pathogenic Unknown; MRI from two affected mutation carriers showed atrophy of the medial temporal lobe. SPECT showed hypoperfusion of the posterior cingulate gyri and other cortical areas. N2a cells transfected with mutant PSEN1 secreted significantly more Aβ42 than cells expressing wild-type PSEN1. The Aβ42:Aβ40 ratio was also increased.

Coding
Exon 6
Point, Missense
TTG to TTC
0 Kasuga et al., 2009
L173F (G>T)
Alzheimer's Disease AD : Pathogenic Unknown. Unknown.

Coding
Exon 6
Point, Missense
TTG to TTT
0 Jin et al., 2012
L173W
Alzheimer's Disease AD : Pathogenic Unknown. Decreased Aβ40 and increased Aβ42 and the Aβ42/Aβ40 ratio in vitro.

rs63750299
Coding
Exon 6
Point, Missense
TTG to TGG
0 Campion et al., 1999
L174del
Alzheimer's Disease AD : Pathogenic Unknown, proband MRI revealed slight temporal lobe atrophy. Increased Aβ40, and decreased Aβ42 and Aβ42/Aβ40 in proband's CSF

Coding
Exon 6
Deletion
CTG to ---
0 Tiedt et al., 2013
L174M
Alzheimer's Disease AD : Pathogenic, CAA : Pathogenic Neuropathology consistent with AD and CAA in one case. Decreased Aβ40 and increased Aβ42/Aβ40 ratio in in vitro experiments. Conservative mutation in third transmembrane domain.

rs63751144
Coding
Exon 6
Point, Missense
CTG to ATG
0 Bertoli Avella et al., 2002;
Tedde et al., 2003
L174R
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD in one case. Also, abundant Lewy bodies in amygdala and entorhinal cortex. Unknown.

rs63751025
Coding
Exon 6
Point, Missense
CTG to CGG
0 Klünemann et al., 2004
F175S
None AD : Not Pathogenic Unknown Unknown

rs63750771
Coding
Exon 6
Point, Missense
TTC to TCC
0 Colacicco et al., 2002
F176L
Alzheimer's Disease AD : Unclear Pathogenicity Neuropathology consistent with AD, notably abundant amyloid plaques and neurofibrillary tangles in the cortex. In fact, the neuropathology in this individual (Auguste D.) defined these structures as hallmarks of AD. Unknown.

Coding
Exon 6
Point, Missense
TTT to CTT
0 Müller et al., 2013
F177L
Alzheimer's Disease AD : Pathogenic Unknown Increased Aβ42 production and Aβ42/Aβ40 ratio in vitro. Little impact on total cleavage activity of γ-secretase.

rs63749911
Coding
Exon 6
Point, Missense
TTT to CTT
0 Rogaeva et al., 2001
F177S
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD. Decreased Aβ42 in CSF of one patient.

rs63749806
Coding
Exon 6
Point, Missense
TTT to TCT
0 Rogaeva et al., 2001
S178P
Alzheimer's Disease AD : Pathogenic Unknown Unknown

rs63750155
Coding
Exon 6
Point, Missense
TCA to CCA
0 Rogaeva et al., 2001
G183V
Pick's disease Other Tauopathy : Pathogenic Severe frontotemporal atrophy; Pick bodies, tau-positive cytoplasmic neuronal inclusions, in the neocortex; A striking absence of extracellular Aβ deposits. Neuropathology was consistent with Pick’s disease. Small increase in Aβ42/Aβ40 ratio; No affect on Notch cleavage; Generates alternative transcripts that lack exon 6 or exons 6 and 7 leading to truncated proteins and possibly to decreased overall levels of PSEN1 protein and loss of function.

rs63751068
Coding
Exon 6
Point, Missense
GGG to GTG
0 Dermaut et al., 2004
E184D
Alzheimer's Disease AD : Pathogenic

rs63750311
Coding
Exon 7
Point, Missense
GAA to GAC
0 Yasuda et al., 1997
E184G
Alzheimer's Disease AD : Pathogenic Unknown. Unknown.

Coding
Exon 7
Point, Missense
GAA to GGA
0 Wallon et al., 2012
V191A
None AD : Not Pathogenic Unknown Unknown

rs112451138
Coding
Exon 7
Point, Missense
GTT to GCT
0 Guerreiro et al., 2010
I202F
Alzheimer's Disease AD : Pathogenic Unknown. Unknown.

Coding
Exon 7
Point, Missense
ATC to TTC
0 Church et al., 2011
G206A
Alzheimer's Disease AD : Pathogenic Typical AD neuropathology, including extensive plaques and tangles (Braak stage VI). Cortical atrophy revealed by MRI and temporo-parietal hypometabolism revealed by FDG-PET. In cells, increased Aβ42; unchanged Aβ40. In assays with isolated proteins, decreased Aβ42 and Aβ40; increased Aβ42/Aβ40 ratio.   

rs63750082
Coding
Exon 7
Point, Missense
GGT to GCT
0 Rogaeva et al., 2001;
Athan et al., 2001
G206D
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD. Unknown.

rs63750082
Coding
Exon 7
Point, Missense
GGT to GAT
0 Raux et al., 2005
G206S
Alzheimer's Disease AD : Pathogenic Unknown; bilateral frontotemporal and parietal hypometabolism by PET; diffuse brain atrophy with enlarged ventricles by CT. Unknown.

rs63750569
Coding
Exon 7
Point, Missense
GGT to AGT
0 Rogaeva et al., 2001;
Raux et al., 2005
G206V
Alzheimer's Disease AD : Pathogenic Unknown; an early MRI of the proband showed mild atrophy of the brain with normal temporal lobes. Unknown.

rs63750082
Coding
Exon 7
Point, Missense
GGT to GTT
0 Goldman et al., 2002
G209A
Alzheimer's Disease AD : Pathogenic Unknown; MRI showed global cortical atrophy and FDG-PET revealed widespread bilateral hypometabolism. Unknown; predicted likely damaging in silico.

Coding
Exon 7
Point, Missense
GGA to GCA
0 An et al., 2016
G209E
Alzheimer's Disease AD : Pathogenic Unknown. Unknown.

rs63750053
Coding
Exon 7
Point, Missense
GGA to GAA
0 Rogaeva et al., 2001
G209R
Alzheimer's Disease AD : Pathogenic Unknown; imaging showed mild brain atrophy in the temporal lobes at early stages and diffuse brain atrophy predominantly in the frontotemporal lobes at advanced stages. Hypoperfusion in the frontotemporal areas at early stages extending to the parieto-occipital areas at advanced stages. Unknown.

rs63749880
Coding
Exon 7
Point, Missense
GGA to AGA
0 Sugiyama et al., 1999
G209V
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD, includin cortical atrophy, extensive amyloid plaques and neurofibrillary tangles, and amyloid angiopathy. Unknown.

rs63750053
Coding
Exon 7
Point, Missense
GGA to GTA
0 Poorkaj et al., 1998
S212Y
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD, including neurofibrillary tangles (Braak stage VI) and frequent neuritic plaques. Severe amyloid angiopathy was noted in the cerebellum and occipital cortex, and α-synuclein pathology was detected in the amygdala. When expressed in HEK293 cells expressing APP with the Swedish mutation, the mutant PSEN1 increased Aβ40, Aβ42, and the Aβ42/Aβ40 ratio compared with cells expressing wild-type PSEN1.

Coding
Exon 7
Point, Missense
TCC to TAC
0 Ringman et al., 2011
I213F
Alzheimer's Disease AD : Pathogenic

rs63750861
Coding
Exon 7
Point, Missense
ATT to TTT
0 Zekanowski et al., 2003
I213L
Alzheimer's Disease AD : Pathogenic Unknown Increased Aβ40 and Aβ42 production, and an increase in the Aβ42:Aβ40 ratio as assessed in vitro.

rs63750861
Coding
Exon 7
Point, Missense
ATT to CTT
0 Rogaeva et al., 2001
I213T
Alzheimer's Disease AD : Pathogenic Unknown. Unknown.

rs63751039
Coding
Exon 7
Point, Missense
ATT to ACT
0 Kamino et al., 1996
H214D
Alzheimer's Disease AD : Pathogenic Unknown Decreased production of both Aβ40 and Aβ42 in vitro; increased Aβ42/Aβ40 ratio.

Coding
Exon 7
Point, Missense
CAC to GAC
0 Clarimón et al., 2008;
Guerreiro et al., 2010
H214N
Alzheimer's Disease AD : Pathogenic Unknown; CT scan showed diffuse cerebral atrophy more pronounced in medial temporal lobes. Unknown; predicted probably damaging in silico.

Coding
Exon 7
Point, Missense
CAC to AAC
0 Piccoli et al., 2016
H214Y
Alzheimer's Disease AD : Pathogenic Unknown; imaging showed global cortical atrophy with marked frontotemporal atrophy and white-matter lesions. Unknown; predicted possibly damaging in silico.

rs63751003
Coding
Exon 7
Point, Missense
CAC to TAC
0 Raux et al., 2005
G217D
Alzheimer's Disease, Parkinsonism AD : Pathogenic Cotton wool plaques.

rs63750444
Coding
Exon 7
Point, Missense
GGT to GAT
0 Miravalle et al., 2002;
Takao et al., 2002
G217R
Alzheimer's Disease AD : Pathogenic Cotton wool plaques.

Coding
Exon 7
Point, Missense
GGT to CGT
0 Norton et al., 2009
L219F
Alzheimer's Disease AD : Pathogenic

rs63749987
Coding
Exon 7
Point, Missense
CTT to TTT
0 Terreni et al., 2016
L219P
Alzheimer's Disease AD : Pathogenic

rs63750761
Coding
Exon 7
Point, Missense
CTT to CCT
0 Smith et al., 1999
L219R
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Unknown.

Coding
Exon 7
Point, Missense
CTT to CGT
0 Ikeda et al., 2013
R220P
Alzheimer's Disease AD : Pathogenic Unknown; MRI showed diffuse cortico-subcortical cerebral atrophy with multiple foci in the deep white matter. Unknown; predicted probably damaging in silico.

Coding
Exon 7
Point, Missense
CGA to CCA
0 Piccoli et al., 2016
Q222H
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD in one case. Aβ42, but not Aβ40, detected in homogenate of proband's frontal cortex.

rs63751072
Coding
Exon 7
Point, Missense
CAG to CAC
0 Miklossy et al., 2003
Q222P
Alzheimer's Disease AD : Pathogenic Unknown Unknown

Coding
Exon 7
Point, Missense
CAG to CCG
0 Scahill et al., 2013;
Ryan et al., 2016
Q222R
Alzheimer's Disease AD : Pathogenic Unknown Unknown

rs63750009
Coding
Exon 7
Point, Missense
CAG to CGG
0 Rogaeva et al., 2001
Q223R
Alzheimer's Disease, Spastic Paraparesis AD : Pathogenic

Coding
Exon 7
Point, Missense
CAG to CGG
0 Uttner et al., 2010
L226F
Alzheimer's Disease, Frontotemporal Dementia AD : Pathogenic Neuropathology consistent with AD. Increased Aβ42/Aβ40 ratio; increased Aβ42; increased Aβ40.

rs63750487
Coding
Exon 7
Point, Missense
CTC to TTC
0 Zekanowski et al., 2006
L226R
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD in one individual, including numerous neuritic plaques and neurofibrillary tangles in the hippocampus and neocortex. Unknown, but consistent with the helical alignment of pathogenic mutations in transmembrane domain 5.

rs63749961
Coding
Exon 7
Point, Missense
CTC to CGC
0 Coleman et al., 2004
I229F
Alzheimer's Disease AD : Pathogenic Unknown In vitro, increased Aβ42 production and reduced Aβ40; increased Aβ42/Aβ40 ratio

rs63749970
Coding
Exon 7
Point, Missense
ATT to TTT
0 Janssen et al., 2003
S230I
Alzheimer's Disease AD : Pathogenic Unknown. Unknown.

Coding
Exon 7
Point, Missense
AGT to ATT
0 Wallon et al., 2012
S230N
Alzheimer's Disease AD : Pathogenic Unknown, but MRI showed diffuse atrophy, which was most severe in lateral temporal lobes and insulae. Unknown, but predicted to be “not tolerated” by SIFT and “Probably Damaging” by PolyPhen-2.

Coding
Exon 7
Point, Missense
AGT to AAT
0 Ringman et al., 2017
S230R
Alzheimer's Disease AD : Pathogenic SPECT imaging showed bilateral parietal hypoperfusion, more marked on the left side. Postmortem evaluation revealed neuropathology consistent with AD, including advanced plaque and tangle pathology (CERAD C, Braak VI). Unknown; predicted possibly damaging in silico.

Coding
Exon 7
Point, Missense
AGT to AGG
0 Sassi et al., 2014
A231P
Alzheimer's Disease AD : Pathogenic Unknown. Unknown; predicted damaging in silico.

Coding
Exon 7
Point, Missense
GCC to CCC
0 Nicolas et al., 2015
A231T
Alzheimer's Disease AD : Pathogenic Unknown Decreased Aβ40 and Aβ42 production and decreased Aβ42/Aβ40 ratio in vitro.

rs63749836
Coding
Exon 7
Point, Missense
GCC to ACC
0 Campion et al., 1995
A231V
Alzheimer's Disease AD : Pathogenic Unknown Unknown, may have a relatively mild effect because substitution is semi-conserved.

rs63750799
Coding
Exon 7
Point, Missense
GCC to GTC
0 Cruts et al., 1998
L232P
Alzheimer's Disease AD : Pathogenic Unknown, but MRI revealed diffuse cortical atrophy, especially in the frontal and parietal lobes. Unknown, but PolyPhen-2 and SIFT predicted that this mutation is likely to be damaging.

Coding
Exon 7
Point, Missense
CTC to CCC
0 Park et al., 2017
M233I (G>A)
Alzheimer's Disease AD : Pathogenic Unknown. Unknown.

Coding
Exon 7
Point, Missense
ATG to ATA
0 Wallon et al., 2012
M233I (G>C)
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with a diagnosis of AD, including amyloid plaques and tau-positive neurofibrillary tangles. No evidence of astrocytic gliosis, spongiosis, or prion disease. Unknown.

rs63751479
Coding
Exon 7
Point, Missense
ATG to ATC
0 Portet et al., 2003
M233L (A>T)
Alzheimer's Disease FTD : Pathogenic Unknown, but SPECT revealed hypoperfusion in posterior pariteal areas and a subsequent PET scan showed hypometabolism in prefrontal, parietal, and temporal cortices, in one case. MRI showed global cerebral atrophy.

rs63751287
Coding
Exon 7
Point, Missense
ATG to TTG
0 Mendez and McMurtray, 2006
M233L (A>C)
Alzheimer's Disease AD : Pathogenic Unknown; imaging showed global cerebral atrophy. In vitro, increased Aβ42 production, decreased Aβ40 production; increased Aβ42:Aβ40 ratio (nucleotide change unknown).

rs63751287
Coding
Exon 7
Point, Missense
ATG to CTG
0 Aldudo et al., 1999
M233T
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD in at least one case. Increased Aβ42, Aβ48, and Aβ39; Decreased Aβ40, Aβ43, and Aβ46.

rs63751024
Coding
Exon 7
Point, Missense
ATG to ACG
1 Kwok et al., 1997
M233V
Alzheimer's Disease AD : Pathogenic Abundant neurofibrillary tangles and amyloid plaques throughout the neocortex; Occasional plaques in the spinal cord; Lewy bodies were observed in the substantia nigra and cortex; Moderate to severe amyloid angiopathy in leptomeningeal, cerebral, and cerebellar vessels. Increased Aβ42/Aβ40 ratio; increased Aβ42; decreased Aβ40.

rs63751287
Coding
Exon 7
Point, Missense
ATG to GTG
0 Houlden et al., 2001
L235P
Alzheimer's Disease, Myoclonus AD : Pathogenic Neuropathology consistent with AD, including a high density of senile plaques and neurofibrillary tangles in the cerebral cortex and hippocampus. Tangles in the basal nucleus of Meynert, septal and raphe nuclei, and the locus coeruleus. Unknown; expresison in transgenic mice was associated with increased production of Aβ, increased tau hyperphosphorylation, and loss of synaptic protein.

rs63749835
Coding
Exon 7
Point, Missense
CTG to CCG
1 Campion et al., 1996
L235R
Alzheimer's Disease AD : Pathogenic Unknown; MRI showed bilateral atrophy, especially in the temporal and parietal lobes. Unknown; predicted possibly damaging in silico.

Coding
Exon 7
Point, Missense
CTG to CGG
0 Antonell et al., 2011
L235V
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD in at least one case. Elevated monoamine-oxidase-A activity.

rs63751130
Coding
Exon 7
Point, Missense
CTG to GTG
0 Janssen et al., 2003
F237I
Alzheimer's Disease, Spastic Paraparesis AD : Pathogenic

rs63750858
Coding
Exon 7
Point, Missense
TTT to ATT
0 Sodeyama et al., 2001
F237L
Alzheimer's Disease AD : Pathogenic Unknown Unknown

rs63750858
Coding
Exon 7
Point, Missense
TTT to CTT
0 Janssen et al., 2003
I238M
Alzheimer's Disease AD : Pathogenic Unknown; MRI showed progressive cerebral atrophy. PET showed hypometabolism in the frontal and temporal lobes. When expressed in HEK293 cells expressing APP with the Swedish mutation, the mutant PSEN1 increased Aβ40, Aβ42, and the Aβ42/Aβ40 ratio compared with cells expressing wild-type PSEN1.

Coding
Exon 7
Point, Missense
ATC to ATG
0 Ting et al., 2014
K239N
Alzheimer's Disease AD : Pathogenic Unknown, but MRI in one case showed medial temporal lobe and frontal lobe atrophy.   In cells, Aβ42 and Aβ42/Aβ40 were increased. However, Aβ40 and Aβ42 production was undetectable in an assay using isolated proteins. 

Coding
Exon 7
Point, Missense
AAG to AAC
0 Lladó et al., 2010
T245P
Alzheimer's Disease AD : Pathogenic Unknown, but MRI showed diffuse brain atrophy in one patient, and no abnormalities in 2 others. Undetectable production of Aβ42 and Aβ40 in in vitro assay using isolated proteins.

rs63750888
Coding
Exon 7
Point, Missense
ACT to CCT
0 Edwards-Lee et al., 2006
A246E
Alzheimer's Disease AD : Pathogenic Generalized atrophy, most prominently in the frontal lobes and hippocampus. Neuronal loss, gliosis, neurofibrillary tangles, and plaques. Increased Aβ42 secretion, Aβ42/Aβ40 ratio, Aβ42/Aβ total ratio. Decreased production of Aβ40 and Aβ42 in vitro. Impaired neuronal differentiation, neural precursor proliferation, viability, autophagy, mitophagy, lysosomal function, ER calcium flux.

rs63750526
Coding
Exon 7
Point, Missense
GCG to GAG
4 Sherrington et al., 1995
A246P
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD (Braak and Braak stage VI, CERAD C) as well as cerebral amyloid angiopathy. Some α-synuclein inclusions were observed in the entorhinal cortex. Unknown; predicted probably damaging in silico.

Coding
Exon 7
Point, Missense
GCG to CCG
0 Roeber et al., 2015
L248P
Alzheimer's Disease AD : Pathogenic Unknown. Unknown; predicted damaging in silico.

Coding
Exon 7
Point, Missense
CTC to CCC
0 Jiao et al., 2014
L248R
Alzheimer's Disease AD : Pathogenic Unknown; in one case, neuroimaging showed prominent atrophy in the lateral fissure, and less prominent in parietofrontal regions Increased Aβ42/Aβ40 ratio, severely decreased production of Aβ40 and Aβ42 in vitro.

Coding
Exon 7
Point, Missense
CTC to CGC
0 Clarimón et al., 2008;
Guerreiro et al., 2010
L250F
Alzheimer's Disease AD : Pathogenic Unknown, but CT scans showed frontal, parietal, and temporal atrophy Unknown

Coding
Exon 7
Point, Missense
TTG to TTT
0 Butler et al., 2010
L250S
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD in two cases. In vitro, decreases Aβ40 and Aβ42 production; increases Aβ42/Aβ40 ratio.

rs63751163
Coding
Exon 7
Point, Missense
TTG to TCG
0 Hutton et al., 1996;
Harvey et al., 1998
L250V
Alzheimer's Disease, Myoclonus AD : Pathogenic, Myoclonus : Pathogenic Unknown, but MRI sohwed diffuse cerebral atrophy and SPECT showed severe cortical hypoperfusion Unknown

rs63750634
Coding
Exon 7
Point, Missense
TTG to GTG
0 Furuya et al., 2003
Y256S
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD in two cases; severe, widespread pathology, including cotton-wool plaques. Increased Aβ40 and Aβ42 in frontal cortex of one case. In vitro, decreased production of Aβ42, and particularly Aβ40; increased Aβ42/Aβ40 ratio.

rs63751320
Coding
Exon 7
Point, Missense
TAT to TCT
0 Miklossy et al., 2003
A260V
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD. Also, perivascular amyloid deposits and Pick-like intra-nueronal inclusions in the dentate gyrus. Reduced production of Aβ40 and Aβ42; increased Aβ42/Aβ40 ratio in cells and in vitro. 

rs63751420
Coding
Exon 8
Point, Missense
GCT to GTT
0 Rogaev et al., 1995;
Ikeda et al., 1996
V261F
Alzheimer's Disease, Spastic Paraparesis AD : Pathogenic Cotton wool plaques.

rs63750964
Coding
Exon 8
Point, Missense
GTT to TTT
0 Rogaeva et al., 2001;
Farlow et al., 2000;
Farlow et al., 2001
V261L
Alzheimer's Disease, Spastic Paraparesis AD : Pathogenic Unknown, but MRI showed cortical and subcortical atrophy, and SPECT revealed temporal hyperperfusion in one patient. Unknown

Coding
Exon 8
Point, Missense
GTT to CTT
0 Jiménez Caballero et al., 2008;
Gómez-Tortosa et al., 2010
L262F
Alzheimer's Disease AD : Pathogenic A brain biopsy from one case "confirmed the diagnosis of AD". Increased Aβ42/Aβ40 ratio in vitro, exhibiting a moderate increase in Aβ42 production, and a decrease in Aβ40 production.

rs63750248
Coding
Exon 8
Point, Missense
TTG to TTC
0 Forsell et al., 1997
L262V
Alzheimer's Disease, Frontotemporal Dementia AD : Pathogenic Unknown. Unknown; predicted probably damaging in silico.

Coding
Exon 8
Point, Missense
TTG to GTG
0 Wallon et al., 2012;
Lohmann et al., 2012
C263F
Alzheimer's Disease AD : Pathogenic Unknown Unknown

rs63751102
Coding
Exon 8
Point, Missense
TGT to TTT
0 Janssen et al., 2003
C263R
Alzheimer's Disease AD : Pathogenic

rs63750543
Coding
Exon 8
Point, Missense
TGT to CGT
0 Wasco et al., 1995
P264L
Alzheimer's Disease, Atypical Dementia, Progressive Nonfluent Aphasia, Spastic Paraparesis AD : Pathogenic Variable: Neuropathology frequently consistent with a diagnosis of AD, but also significant white-matter abnormalities and severe cerebral amyloid angiopathy with numerous small cortical infarcts. Abundant cotton-wool plaques composed of Aβ42 have also been reported. Moderately increased in Aβ42/Aβ40 ratio; increased Aβ42; Deposition of presenilin-1 protein in the endoplasmic reticulum, leading to reduced γ-secretase activity.

rs63750301
Coding
Exon 8
Point, Missense
CCG to CTG
1 Campion et al., 1995;
Wasco et al., 1995
G266S
Alzheimer's Disease, Cerebral Amyloid Angiopathy, Spastic Paraparesis AD : Pathogenic, CAA : Pathogenic In one case, cotton-wool plaques; cerebral amyloid angiopathy; temporal and frontal lobe atrophy; widespread NFTs; reactive gliosis in white matter. MRI in another case revealed parietal lobe atrophy, frontal lobe deep white matter abnormalities. SPECT showed hypoperfusion of parietal and occipital areas. Marked increase in Aβ42/Aβ40 ratio; reduced production of Aβ42, and particularly Aβ40, in vitro. 

rs121917807
Coding
Exon 8
Point, Missense
GGT to AGT
0 Matsubara-Tsutsui et al., 2002;
Akatsu et al., 2008
P267A
Alzheimer's Disease AD : Pathogenic Frequent neuritic plaques, including in the neocortex (Braak stage VI); Severe cerebral amyloid angiopathy. Unknown; predicted probably damaging in silico.

Coding
Exon 8
Point, Missense
CCA to GCA
0 Ringman et al., 2016
P267L
Alzheimer's Disease AD : Pathogenic Unknown. Unknown.

rs63750779
Coding
Exon 8
Point, Missense
CCA to CTA
0 Kowalska et al., 2003
P267S
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with Alzheimer's disease. Reduced γ-secretase activity; Increased cell cycle arrest.

rs63751229
Coding
Exon 8
Point, Missense
CCA to TCA
0 , 1995;
Hutton et al., 1996
R269G
Alzheimer's Disease, Myoclonus AD : Pathogenic Unknown, but in one patient, MRI showed mild, non-specific cortical atrophy and EEG revealed a moderate, bilateral excess of slow wave activity. SPECT imaging showed non-specific, moderate hypoperfusion of the posterior parietal cortex.   Decreased Aβ40 and Aβ42 production; increased Aβ42/Aβ40 ratio. 

rs63751019
Coding
Exon 8
Point, Missense
CGT to GGT
0 Perez-Tur et al., 1996
R269H
Alzheimer's Disease, Myoclonus AD : Pathogenic Neuropathology consistent with Alzheimer's disease; a high burden of Aβ and neurofibrillary tangles in cortical areas. Unknown.

rs63750900
Coding
Exon 8
Point, Missense
CGT to CAT
0 Gómez-Isla et al., 1997
L271V
Alzheimer's Disease AD : Pathogenic Considerable atrophy of the temporal and posterior white matter with enlargement of the lateral ventricles. Variant plaques: large, non-cored, reminiscent of cotton-wool plaques. Depigmented locus coeruleus.

Affects splicing of exon 8 such that more transcripts are produced which lack exon 8. Causes amino acid replacement (D257A) at the splice junction of exons 7 and 9.
 


rs63750886
Coding
Exon 8
Point, Missense
CTG to GTG
0 Kwok et al., 2003
V272A
Alzheimer's Disease, Parkinsonism, Subcortical Dementia AD : Pathogenic Neuropathology consistent with AD, but also Lewy bodies in cortex and substantia nigra, and widespread subcortical neuritic lesions. MRI and PET abnormalities in subcortical-frontal areas in later stages of disease. Increased plasma Aβ42. In vitro, increased Aβ42 production and Aβ42/Aβ40.

rs63750680
Coding
Exon 8
Point, Missense
GTT to GCT
0 Jimenez-Escrig et al., 2004
E273A
Alzheimer's Disease AD : Pathogenic Unknown Increased Aβ42 and Aβ42/Aβ40 ratio in vitro; disrupted calcium flow in ER.

rs63750772
Coding
Exon 8
Point, Missense
GAA to GCA
0 Kamimura et al., 1998
E273G
Alzheimer's Disease AD : Pathogenic Unknown. Unknown.

Coding
Exon 8
Point, Missense
GAA to GGA
0 Wallon et al., 2012
T274R
Alzheimer's Disease AD : Pathogenic Unknown In vitro, Aβ40 and Aβ42 production was undetectable.

rs63750284
Coding
Exon 8
Point, Missense
ACA to AGA
0 Rogaeva et al., 2001
A275V
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD. Unknown.

Coding
Exon 8
Point, Missense
GCT to GTT
0 Luedecke et al., 2014
R278I
Alzheimer's Disease, Progressive Nonfluent Aphasia AD : Pathogenic, Progressive Nonfluent Aphasia : Pathogenic Unknown; MRI showed multiple white-matter foci; Atrophy minimal or absent. Deficient maturation of mutant protein in iPSC-derived neurons. Selective increase in secreted Aβ43; impaired endoproteolysis of PSEN1. Increased Aβ42/Aβ40, Aβ42/Aβ38, and particularly Aβ43/Aβ40 ratios. Aβ38/Aβ40 ratio similar to wild-type.  Impaired processing of the ApoER2 LDL receptor.   

rs63749891
Coding
Exon 8
Point, Missense
AGA to ATA
1 Godbolt et al., 2004
R278K
Alzheimer's Disease, Spastic Paraparesis AD : Pathogenic, SP : Pathogenic Unknown; MRI and CT scans reported as normal in one individual Increased Aβ42 production in patient fibroblasts; but reduced Aβ42 and Aβ40 production in assay with purified proteins. In both cases, increased Aβ42/Aβ40.

rs63749891
Coding
Exon 8
Point, Missense
AGA to AAA
0 Assini et al., 2003
R278S
Alzheimer's Disease, Spastic Paraparesis AD : Pathogenic Unknown Unknown

rs63750524
Coding
Exon 8
Point, Missense
AGA to AGC
0 Raman et al., 2007
R278T
Alzheimer's Disease, Spastic Paraparesis AD : Pathogenic Neuropathology consistent with AD was detected in one brain biopsy. Unknown

rs63749891
Coding
Exon 8
Point, Missense
AGA to ACA
0 Kwok et al., 1997
E280A
(Paisa)
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD, including severe brain atrophy, Aβ pathology, and hyperphosphorylated tau tangles. Aβ42 may be particularly abundant in the cerebral cortex, hippocampus, cerebellum, midbrain, and basal ganglia. Frequent CAA and cerebellar damage including ubiquitin–positive plaques, reactive astrocytes, and dystrophic neurites. Increased Aβ42/Aβ40 ratio; increased Aβ42 in cells; isolated proteins produce less Aβb40 and Aβb42. Reduced proteolytic processing of the Nav sodium channel in cells.

rs63750231
Coding
Exon 8
Point, Missense
GAA to GCA
0 , 1995;
Lopera et al., 1997;
Lemere et al., 1996
E280G
Alzheimer's Disease, Spastic Paraparesis AD : Pathogenic Frequent cotton-wool plaques and vascular amyloid deposits; Some cases with white-matter abnormalities and degeneration of the corticospinal tract. Increased Aβ42/Aβ40 ratio; increased Aβ42.

rs63750231
Coding
Exon 8
Point, Missense
GAA to GGA
0 , 1995;
O'Riordan et al., 2002
E280K
Alzheimer's Disease AD : Pathogenic Unknown; MRI showed generalized brain atrophy, including atrophy of the hippocampus. Unknown; predicted probably damaging in silico.

Coding
Exon 8
Point, Missense
GAA to AAA
0 Ch'ng et al., 2015
L282F
Alzheimer's Disease AD : Pathogenic Unknown; MRI showed mild medial temporal atrophy. FDG-PET showed glucose hypometabolism in the bilateral parietal cortices and posterior cingulate gyri. Unknown.

Coding
Exon 8
Point, Missense
CTT to TTT
0 Hamaguchi et al., 2009
L282R
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with Alzheimer's disease. Unknown.

rs63750050
Coding
Exon 8
Point, Missense
CTT to CGT
0 Aldudo et al., 1998
L282V
Alzheimer's Disease, Cerebral Amyloid Angiopathy AD : Pathogenic Extensive neurofibrillary tangles and amyloid deposits including both dense-cored plaques and diffuse plaques. Severe cerebral amyloid angiopathy (CAA) in the neocortex, hippocampus, and cerebellum. CAA deposits associated with dystrophic neurites and inflammatory gliosis. Severe white-matter loss. Cerebellar amyloid pathology associated with severe CAA and loss of Purkinje cells. A twofold increase in the Aβ42/Aβ40 ratio compared with cells expressing wild-type PSEN1.

rs63749937
Coding
Exon 8
Point, Missense
CTT to GTT
0 Dermaut et al., 2001
F283L
Corticobasal Syndrome AD : Pathogenic, CBS : Pathogenic Neuropathology consistent with AD; absence of CBD pathology (2 cases in 1 family). MRI showed severe parietal, perirolandic, and temporal atrophy with relative sparing of frontal and ipsilateral hippocampal regions. Unknown, but predicted to have a damaging effect according to SIFT, Polyphen, and Mutation Taster.

Coding
Exon 8
Point, Missense
TTT to TTG
0 Scahill et al., 2013;
Ryan et al., 2016
P284L
Alzheimer's Disease, Spastic Paraparesis AD : Pathogenic Prominent cotton-wool plaques in the cerebral cortex, basal ganglia, brainstem, and spinal cord. Some dense core plaques, primarily in the hippocampus and cerebral cortex. Vacuolar changes. Amyloid angiopathy. Neurofibrillary tangles. Mild neuritic changes and gliosis. Unknown.

rs63750863
Coding
Exon 8
Point, Missense
CCA to CTA
0 Tabira et al., 2002
P284S
Alzheimer's Disease, Spastic Paraparesis AD : Pathogenic Unknown, but MRI revealed widespread white-matter lesions in 4 family members, and lobar microbleeds in two members.  Aβ40 and Aβ42 production was similar to wild-type PSEN1 in vitro.

rs63750324
Coding
Exon 8
Point, Missense
CCA to TCA
0 Marrosu et al., 2006
A285V
Alzheimer's Disease AD : Pathogenic Unknown, but MRI from 2 patients showed atrophy of the temporo-parietal cortex and hippocampus, and abnormalities in the deep white matter of the pariteo-occipital lobes. SPECT revealed hypoperfusion in parietal and occipital areas. Aβ40 and Aβ42 levels similar to controls in CSF of one patient. In cells, Aβ42 production elevated compared to Aβ40 and Aβ38 production. In vitro, both Aβ40 and Aβ42 production modestly reduced; Aβ42/Aβ40 similar to wild-type PSEN1.

rs63751139
Coding
Exon 8
Point, Missense
GCT to GTT
0 Ikeda et al., 1996
L286P
Alzheimer's Disease, Cerebral Amyloid Angiopathy AD : Pathogenic, CAA : Pathogenic

Coding
Exon 8
Point, Missense
CTC to CCC
0 Sánchez-Valle et al., 2007
L286V
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD. Increased Aβ42/Aβ total ratio in cells. In vitro, decreased Aβ40 and Aβ42 production. Disrupts intracellular calcium dynamics.

rs63751235
Coding
Exon 8
Point, Missense
CTC to GTC
10 Sherrington et al., 1995
T291A
Alzheimer's Disease AD : Unclear Pathogenicity, Parkinsonism : Unclear Pathogenicity Unknown, patient with 2 PSEN1 mutations (A434T, T291A) had AD pathology with cotton wool plaques, diffuse deposits, and severe amyloid angiopathy Unknown

Coding
Exon 9
Point, Missense
ACA to GCA
0 Ryan et al., 2016
T291P
Alzheimer's Disease, Spastic Paraparesis AD : Pathogenic Unknown; MRI showed marked diffuse atrophy and a signal in the right temporal lobe, compatible with previous bleeding. Point mutation in exon 8 that affects exon 9 splicing, leading to a minor transcript in which exon 9 is excluded. In vitro, this mutation increases both Aβ40 and Aβ42, with a greater effect on Aβ42 and an overall increase in the Aβ42/Aβ40 ratio.

rs63750298
Coding
Exon 8
Point, Missense
ACA to CCA
0 Dumanchin et al., 2006
K311R
Alzheimer's Disease AD : Pathogenic Unknown Increased Aβ42 and reduced Aβ40 levels in conditioned media of cultured cells, resulting in increased Aβ42:Aβ40. Also increased phosphorylated tau levels in cell lysates.

rs115865530
Coding
Exon 9
Point, Missense
AAA to AGA
0 Dong et al., 2017
E318G
None AD : Risk Modifier Unknown. Mixed results. Some carriers have increased CSF tau and phospho-tau; increased plasma Aβ40. In vitro, reduced production of Aβ40 and Aβ42, but increased secretion of both peptides in cells.

RS17125721
Coding
Exon 9
Point, Missense
GAA to GGA
0 Sandbrink et al., 1996;
Cruts et al., 1998;
Aldudo et al., 1998
D333G
Dilated Cardiomyopathy AD : Unclear Pathogenicity Unknown Aβ42 production slightly reduced in vitro. Altered calcium signaling in fibroblasts.

rs121917809
Coding
Exon 10
Point, Missense
GAT to GGT
0 Li et al., 2006
R352C
Alzheimer's Disease AD : Unclear Pathogenicity Unknown; imaging showed cerebral global atrophy. Unknown.

Coding
Exon 10
Point, Missense
CGC to TGC
0 Jiang et al., 2015
R352_S353insR
Frontotemporal Dementia FTD : Unclear Pathogenicity Unknown, single case with confirmed mutation had FTD symptoms and pathology, but was subsequently found to also have a progranulin mutation In-frame insertion of 3 nucleotides in exon 10 resulting in insertion of an arginine between amino acids R352 and S353. Aβ CSF and plasma levels in proband are roughly normal. In cultured cells, expression of insR352 increased the Aβ42:Aβ40 ratio, but markedly reduced the levels of both secreted Aβ40 and Aβ42.

rs63750762
Coding
Exon 10
Insertion
CGC.TCT to CGC.CGC.TCT
0 Rogaeva et al., 2001;
Tang-Wai et al., 2002;
Amtul et al., 2002
T354I
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Unknown.

rs63751164
Coding
Exon 10
Point, Missense
ACA to ATA
0 Rogaeva et al., 2001;
Lee et al., 2006
R358Q
Alzheimer's Disease AD : Pathogenic Unknown In vitro, increased Aβ42/Aβ40; decreased Aβ40 and Aβ42 production

rs63751174
Coding
Exon 10
Point, Missense
CGA to CAA
0 Rogaeva et al., 2001
S365A
Alzheimer's Disease AD : Pathogenic Unknown In vitro production of Aβ38, Aβ40, Aβ42, and Aβ43 similar to wildtype. However, the phosphorylation status of this site appears to modulate a PSEN1 calcium-triggered conformational change linked to increased Aβ42/Aβ40.

Coding
Exon10
Point, Missense
TCC to GCC
0 Clarimón et al., 2008;
Guerreiro et al., 2010
S365Y
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Unknown.

rs63750941
Coding
Exon 10
Point, Missense
TCC to TAC
0 Rogaeva et al., 2001
R377M
Alzheimer's Disease AD : Pathogenic Unknown Unknown

rs63751051
Coding
Exon 11
Point, Missense
AGG to ATG
0 Janssen et al., 2003
R377W
Alzheimer's Disease AD : Pathogenic Unknown; imaging showed frontotemporal atrophy and hypometabolism. Unknown; predicted damaging in silico.

Coding
Exon 10
Point, Missense
AGG to TGG
0 Wallon et al., 2012;
Borroni et al., 2011
G378E
Alzheimer's Disease, Cerebral Amyloid Angiopathy AD : Pathogenic, CAA : Pathogenic Neuropathology consistent with AD. One case also had notable cerebral amyloid angiopathy. Increased Aβ42/Aβ40 ratio; increased Aβ42.

rs63750323
Coding
Exon 11
Point, Missense
GGA to GAA
0 Besançon et al., 1998
G378V
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD. Unknown.

rs63750323
Coding
Exon 11
Point, Missense
GGA to GTA
0 Janssen et al., 2003
G378fs
Alzheimer's Disease AD : Unclear Pathogenicity Unknown; MRI showed hippocampal and parahippocampal atrophy. Unknown; the insertion of one nucleotide in exon 11 is predicted to cause a frameshift.

Coding
Exon 11
Insertion
GGA.GTA to GGG.AGT
0 El Kadmiri et al., 2014
L381F
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD, including neuritic amyoid plaques and neurofibrillary tangles. Hirano bodies and granulovacuolar degeneration in the hippocampus. In silico analysis suggests that the mutation affects the folding free energy and flexibility of the protein.

Coding
Exon 11
Point, Missense
CTT to TTT
0 Dolzhanskaya et al., 2014
L381V
Alzheimer's Disease, Spastic Paraparesis AD : Pathogenic Unknown. Increased Aβ42/Aβ40 ratio; increased Aβ42; Reduced presenilin-1 N-terminal fragment (NTF), suggesting impaired endoproteolysis of presenilin-1.

rs63750687
Coding
Exon 11
Point, Missense
CTT to GTT
0 Dintchov Traykov et al., 2009;
Mehrabian et al., 2004
G384A
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD. Increased Aβ42/Aβ40 ratio; increased Aβ42; decreased Aβ40.

rs63750646
Coding
Exon 11
Point, Missense
GGA to GCA
0 Cruts et al., 1995;
Tanahashi et al., 1996
F386I
Alzheimer's Disease AD : Pathogenic Unknown; MRI showed atrophy of hippocampus.
 
Unknown; predicted damaging in silico.

Coding
Exon 11
Point, Missense
TTC to ATC
0 Shea et al., 2017
F386S
Alzheimer's Disease AD : Pathogenic Unknown Increased Aβ42/Aβ40 ratio in cells and in vitro. In vitro assays indicated reduced production of both Aβ40 and Aβ42; cell-based assays showed increased secretion of both peptides.

rs63749860
Coding
Exon 11
Point, Missense
TTC to TCC
0 Raux et al., 2005
F388L
Alzheimer's Disease AD : Pathogenic Unknown. Increased Aβ42 and Aβ42/Aβ40 ratio.

Coding
Exon 11
Point, Missense
TTC to TTG
0 Zhan et al., 2017
S390I
Alzheimer's Disease AD : Pathogenic Unknown Drastic decrease in production of both Aβ40 and Aβ42 in vitro.

rs63750883
Coding
Exon 11
Point, Missense
AGT to ATT
0 Campion et al., 1999
S390N
Alzheimer's Disease AD : Pathogenic Unknown; MRI showed cerebral amyloid angiopathy. Unknown.

Coding
Exon 11
Point, Missense
AGT to AAT
0 Nicolas et al., 2015
V391F
Alzheimer's Disease AD : Pathogenic Unknown Increased Aβ42/Aβ40 ratio; reduced Aβ40 production in vitro.

rs63751066
Coding
Exon 11
Point, Missense
GTT to TTT
0 Raux et al., 2005
V391G
Alzheimer's Disease AD : Pathogenic, Parkinsonism : Unknown; in single case MRI showed generalized mild cortical and subcortical atrophy, thinner hippocampus, and enlarged ventricles. Unknown, probable damaging as predicted by SIFT, Poly-Phen-2, and Mutation Taster. Phenotype complicated by family history of extrapyramidal disease with several associated recessive mutations (PANK2, SYNE1, ZNF592)

Coding
Exon 11
Point, Missense
GTT to GGT
0 Lou et al., 2017
L392P
Alzheimer's Disease AD : Pathogenic

rs63750218
Coding
Exon 11
Point, Missense
CTG to CCG
0 Tedde et al., 2000;
Sorbi et al., 2002
L392V
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD, including cortical atrophy, amyloid plaques, and neurofibrillary tangles. Increased Aβ42:Aβ40 ratio; increased Aβ42. The mutant protein also had impaired endoproteolysis and resulted in lower NICD production, suggesting reduced Notch cleavage by γ-secretase.

rs63751416
Coding
Exon 11
Point, Missense
CTG to GTG
0 Campion et al., 1995;
Campion et al., 1995;
Rogaev et al., 1995;
Campion et al., 1999
G394V
Alzheimer's Disease AD : Pathogenic Unknown In vitro, Aβ40 production undetectable; Aβ42 drastically reduced. In patient cells with additional mutation (E318G), no change in Aβ40 or Aβ42 levels.

rs63750929
Coding
Exon 11
Point, Missense
GGT to GTT
0 Rogaeva et al., 2001
A396T
Alzheimer's Disease AD : Pathogenic Unknown; MRI of the proband showed atrophy of the frontal lobes. Increased Aβ42 production in cells; reduced Aβ40 production and increased Aβ42/Aβ40 ratio in vitro. Predicted probably damaging in silico.

Coding
Exon 11
Point, Missense
GCC to ACC
0 Lohmann et al., 2012
N405S
Alzheimer's Disease AD : Pathogenic

rs63751254
Coding
Exon 11
Point, Missense
AAC to AGC
0 Yasuda et al., 2000
I408T
Alzheimer's Disease AD : Pathogenic Unknown; MRI of the proband showed marked enlargement of the lateral ventricles and hippocampal atrophy typical of AD. Unknown; predicted damaging in silico.

Coding
Exon 11
Point, Missense
ATA to ACA
0 Tedde et al., 2016
A409T
Alzheimer's Disease AD : Pathogenic Unknown Decreased Aβ40 and Aβ42 production and decreased Aβ42/Aβ40 ratio in vitro.

rs63750227
Coding
Exon 11
Point, Missense
GCC to ACC
0 Aldudo et al., 1999
C410Y
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD. Increased Aβ42/Aβ total ratio; decreased production of Aβ42, Aβ40, NTF, CTF, AICD. Conflicting data on Aβ43 production. Dominant-negative inhibition of Aβ peptide production by wild-type PSEN1. Partial loss of γ-secretase mediated cleavage of Notch and β-neurexin.

rs661
Coding
Exon 11
Point, Missense
TGT to TAT
0 Sherrington et al., 1995;
Campion et al., 1995
V412I
Frontotemporal Dementia FTD : Pathogenic Unknown; in one case, 18FDG-PET showed hypometabolism in the parietal and frontal cortices, as well as in the putamen and caudate. In another case, SPECT showed widespread cortical hypoperfusion.  Severe decrease in Aβ42 and undetectable Aβ40 levels in in vitro assay using isolated proteins.

Coding
Exon 11
Point, Missense
GTA to ATA
0 Bernardi et al., 2009
I416T
Alzheimer's Disease AD : Pathogenic Unknown, but two cognitively normal mutation carriers had preclinical amyloid plaques and tau accumulation, as assessed by PET, similar to those of individuals at-risk for late-onset AD or individuals carrying other AD-causing PSEN1 mutations. Unknown, but mutation results in the substitution of a highly conserved, transmembrane, hydrophobic amino acid with a polar amino acid near a splice site. Computational algorithms (SIFT, PolyPhen2 HDIV and HVAR, MutationTaster, FATHMM, MetaSVM, PROVEAN, and REVEL) predict deleteriousness.

Coding
Exon 12
Point, Missense
ATT to ACT
0 Ramirez Aguilar et al., 2019
G417S
Alzheimer's Disease AD : Pathogenic, SP : Pathogenic Cotton wool plaques throughout cortex, abundant Aβ deposits in cerebellum and spinal gray matter (one patient). Also, CAA, extensive neuronal loss, astrocytic and microglial markers, and extensive distribution of neocortical Lewy bodies. TDP-43 inclusions in limbic region and temporal cortex. Unknown

Coding
Exon 12
Point, Missense
GGT to AGT
0 Miki et al., 2019
L418F
Alzheimer's Disease AD : Pathogenic Unknown Decreased Aβ40 and Aβ42 production, and elevated Aβ42/Aβ40 ratio, in vitro.

rs63751316
Coding
Exon 11
Point, Missense
TTG to TTT
0 Rogaeva et al., 2001
L420R
Alzheimer's Disease AD : Pathogenic Extensive amyloid pathology, primarily in the form of cotton-wool plaques, although some rare dense core plaques. Some amyloid angiopathy. Unknown.

rs63750802
Coding
Exon 12
Point, Missense
CTT to CGT
0 Shrimpton et al., 2007
L424F
Alzheimer's Disease AD : Pathogenic Unknown, but neuroimaging in two patients revealed brain atrophy with white-matter changes. Unknown

Coding
Exon 12
Point, Missense
CTC to TTC
0 Mehrabian et al., 2006
L424H
Alzheimer's Disease, Atypical Dementia AD : Pathogenic Unknown; generalized cerebral atrophy by MRI; diffuse cerebral hypoperfusion by SPECT.

rs63751032
Coding
Exon 12
Point, Missense
CTC to CAC
0 Raux et al., 2005;
Zekanowski et al., 2006
L424R
Alzheimer's Disease AD : Pathogenic Unknown; MRI showed cortical and subcortical atrophy with a thin corpus callosum. Unknown.

rs63751032
Coding
Exon 12
Point, Missense
CTC to CGC
0 Kowalska et al., 1999
L424V
Atypical Dementia AD : Pathogenic, Atypical Dementia : Pathogenic Unknown; CT and SPECT imaging showed diffuse cortical and subcortical atrophy and hypoperfusion affecting the frontal, temporal, and parietal lobes. Unknown.

Coding
Exon 12
Point, Missense
CTC to GTC
0 Robles et al., 2009
A426P
Alzheimer's Disease AD : Pathogenic Unknown, but PiB-PET revealed robust amyloid deposition in the striatum. PiB retention was also found in the neocortex and thalamus. Compared to sporadic AD, amyloid accumulation in frontal, temporoparietal, and precuneus cortices was lower. Slight decrease in Aβ40 and Aβ42 production in vitro; Aβ42/Aβ40 ratio similar to controls. In silico analyses predicted the mutation to be tolerated (SIFT) and probably damaging (Polyphen2). 

rs63751223
Coding
Exon 12
Point, Missense
GCC to CCC
0 Poorkaj et al., 1998
A431E
(Jalisco)
Alzheimer's Disease AD : Pathogenic, SP : Pathogenic Neuropathology consistent with AD. Widespread white-matter abnormalities in 3 patients with spastic paraparesis.  Reduced Aβ37, Aβ38, Aβ39, Aβ40, and Aβ42 levels, as well as Aβ42/Aβ40 ratio, in CSF. Increased Aβ42 in plasma. In vitro, reduced production of Aβ40 and Aβ42. Enhances MAO-A activity in cells.

rs63750083
Coding
Exon 12
Point, Missense
GCA to GAA
0 Rogaeva et al., 2001;
Yescas et al., 2006
A431V
Alzheimer's Disease AD : Pathogenic

rs63750083
Both
Exon 12
Point, Missense
GCA to GTA
0 Matsushita et al., 2002
A434C
Alzheimer's Disease AD : Pathogenic Numerous diffuse plaques and neuritic plaques with dense amyloid cores throughout the neocortex; Abundant neurofibrillary tangles and Hirano bodies; Moderate cell loss and gliosis in the hippocampus, amygdala, and nucleus basalis. Unknown.

rs63750528, rs63750341
Coding
Exon 12
Point, Double
GCT to TGT
0 Devi et al., 2000
A434T
Alzheimer's Disease AD : Pathogenic Unknown. Unknown; predicted damaging in silico.

Coding
Exon 12
Point, Missense
GCT to ACT
0 Jiao et al., 2014
L435F
Alzheimer's Disease AD : Pathogenic Widespread cotton-wool plaques in the neocortex, hippocampus, and deep cerebral nuclei contain substantially more Aβ43 than typical plaques. Abundant neurofibrillary tangles in the entorhinal cortex and hippocampus. Mild cerebral amyloid angiopathy. Neuronal loss, depigmentation, and gliosis in the substantia nigra. Decreased Aβ42, Aβ40, APP-CTF, Notch-1 ICD. Elevated Aβ43 in cells and human brain tissue, but decreased Aβ43 in knockin mice. Impairs wildtype PSEN1 γ-secretase activity.

rs63750001
Coding
Exon 12
Point, Missense
CTT to TTT
0 Rogaeva et al., 2001
P436Q
Alzheimer's Disease, Spastic Paraparesis AD : Pathogenic Neuropathology consistent with AD in at least one mutation carrier, including frequent Aβ plaques, many of the cotton-wool type, and severe neurofibrillary tangle pathology (Braak and Braak stage VI). Unknown.

rs121917808
Coding
Exon 12
Point, Missense
CCA to CAA
0 Taddei et al., 1998
P436S
Alzheimer's Disease AD : Pathogenic Unknown Increased Aβ42/Aβ40 ratio in cells and in vitro. In cells, decreased production of Aβ40, Aβ42, AICD, Notch. In vitro, decreased Aβ40, with no effect on Aβ42 production.

rs63749925
Coding
Exon 12
Point, Missense
CCA to TCA
0 Palmer et al., 1999
I437V
Alzheimer's Disease AD : Pathogenic Unknown. Unknown.

Coding
Exon 12
Point, Missense
ATC to GTC
0 Nicolas et al., 2015
I439S
Alzheimer's Disease AD : Pathogenic Unknown, but MRI showed diffuse cortical atrophy in one case. Unknown, but PolyPhen analysis predicted the mutation is possibly damaging.

Coding
Exon 12
Point, Missense
ATC to AGC
0 Gómez-Tortosa et al., 2010
I439V
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Unknown.

rs63750249
Coding
Exon 12
Point, Missense
ATC to GTC
0 Rogaeva et al., 2001
T440del
Alzheimer's Disease, Dementia with Lewy Bodies AD : Pathogenic Cotton-wool plaques. Trinucleotide deletion; deletion of 1 amino acid.

rs63750470
Coding
Exon 12
Deletion
ACC to ---
0 Ishikawa et al., 2005
869-2A>G
Behavioral variant FTD bvFTD : Pathogenic Unknown Reduced Aβ42 in CSF of one individual, predicted pathogenic by CADD and DANN in silico analyses.

Non-Coding
Intron 8/11
Point
0 Blauwendraat et al., 2017
869-22_869-23ins18
(ΔE9, Δ9, deltaE9)
Alzheimer's Disease, Spastic Paraparesis AD : Pathogenic Cotton-wool plaques in addition to widespread neurofibrillary tangles and neuritic plaques more typical of AD. Marked cerebral amyloid angiopathy. Insertion of 18 nucleotides (TGGAATTTTGTGCTGTTG) in intron 8, between nucleotide 23 and 22 upstream of exon 9, resulting in exon 9 skipping.

Both
Intron 8, Exon 9
Insertion
0 Dumanchin et al., 2006
I238_K239insI
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD (Braak and Braak stage VI, CERAD C). Cortical atrophy, mainly of the frontal lobe; Numerous neurofibrillary tangles and amyloid plaques, as well as ghost tangles, neuropil threads, and neuritic plaques; Cerebral amyloid angiopathy. Unknown; insertion of the trinucleotide TAA results in the insertion of one amino acid (isoleucine), but does not cause a frameshift. In silico this insertion is predicted to be deleterious.

Coding
Exon 7
Insertion
AAG to ATAAAG
0 Roeber et al., 2015
S290C;T291_S319del
(ΔE9Finn, Δ9Finn, Δ9)
Alzheimer's Disease, Spastic Paraparesis AD : Pathogenic Variable across two families: One family had unusual plaques described as “reminiscent of loosely packed cotton-wool balls” which were large (100-150 μM in diameter) and not congophilic, suggesting a lack of amyloid at the core, in addition to more typical AD plaques and tangles. The other family had more typical AD pathology. This is a 4.6 kb deletion including the entire exon 9 and extending into the flanking intronic sequences. It results in the in-frame skipping of exon 9 and an amino acid substitution at the splice junction of exons 8 and 10 (S290C).

Both
Intron 8, Exon 9
Complex
0 Crook et al., 1998;
Prihar et al., 1999
S290C;T291_S319del
(ΔE9, Δ9)
Alzheimer's Disease, Spastic Paraparesis AD : Pathogenic Variable: lesions observed include cotton-wool plaques, cored plaques, and tangles. Corticospinal tract degeneration, cortical atrophy, and congophilic amyloid angiopathy also variably observed. This is a 5.9 kb deletion including the entire exon 9 and extending into the flanking intronic sequences. It results in the in-frame skipping of exon 9 and an amino acid substitution at the splice junction of exons 8 and 10 (S290C).

Both
Intron 8, Exon 9
Complex
0 Smith et al., 2001
S290C;T291_S319del A>G
(ΔE9, Δ9)
Alzheimer's Disease AD : Pathogenic Unknown; MRI showed supratentorial atrophy, particularly of parietal and occipital cortex. Point mutation in a splice acceptor site in intron 8 resulting in in-frame skipping of exon 9 and an amino acid change at the splice junction of exon 8 and 10 (S290C).

Both
Intron 8, Exon 9
Complex
0 Rovelet-Lecrux et al., 2015
S290C;T291_S319del G>A
(ΔE9, Δ9)
Alzheimer's Disease, Spastic Paraparesis AD : Pathogenic Cotton-wool plaques are common, in addition to classic neuritic, amyloid plaques. Tangles, neuronal loss, atrophy typical of AD. Point mutation in a splice acceptor site in intron 8 resulting in an in-frame skipping of exon 9 and an amino acid change at the splice junction of exons 8 and 10 (S290C).

rs63750219
Both
Intron 8, Exon 9
Complex
0 Sato et al., 1998
S290C;T291_S319del G>T
(ΔE9, Δ9)
Alzheimer's Disease, Spastic Paraparesis AD : Pathogenic Cotton-wool plaques throughout the neocortex. Less frequent cored plaques. Neurofibrillary tangles, some neuronal loss, gliosis, and cerebral amyloid angiopathy. Point mutation in a splice acceptor site in intron 8 resulting in in-frame skipping of exon 9 and an amino acid change at the splice junction of exon 8 and 10 (S290C).

rs63750219 
Both
Intron 8, Exon 9
Complex
0 Perez-Tur et al., 1995;
Hutton et al., 1996
S290W;S291_R377del
(Δ9-10 , Delta9-10, p.Ser290_Arg377delinsTrp, g.73671948_73682054del)
Alzheimer's Disease, Spastic Paraparesis Early-onset : Pathogenic No data. This mutation involves the deletion of 10.1 kilobases including exons 9 and 10. A S290W missense mutation is predicted at the junction between exons 8 and 11.

Both
Introns 8-10, Exons 9-10
Deletion
0 Le Guennec et al., 2017

PSEN2 (48)

The gene PSEN2 encodes presenilin-2, a subunit of γ-secretase, the aspartyl protease responsible for Aβ generation. Missense mutations in PSEN2 are a rare cause of early onset Alzheimer's disease.

Mutation Clinical
Phenotype
Pathogenicity Neuropathology Biological Effect Genomic Position Genomic Region Mutation Type
Codon Change
Research
Models
Primary
Papers
T18M
Parkinson's Disease PD : Unclear Pathogenicity Unknown. Unknown; predicted pathogenic in silico.

rs143061887
Coding
Exon 3
Point, Missense
ACG to ATG
0 Blauwendraat et al., 2016
R29H
None AD : Not Pathogenic Not applicable. Unknown.

Coding
Exon 3
Point
CGC to CAC
0 Guerreiro et al., 2010
G34S
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Unchanged Aβ42/Aβ40 ratio.

Coding
Exon 3
Point
GGC to AGC
0 Sleegers et al., 2004
R62C
Alzheimer's Disease, None AD : Unclear Pathogenicity Unknown. Unknown; predicted possibly damaging in silico.

rs150400387
Coding
Exon 4
Point
CGC to TGC
0 Sleegers et al., 2004;
Ertekin-Taner et al., 2008;
Brouwers et al., 2008
R62H
Alzheimer's Disease, Frontotemporal Dementia, Parkinson's Disease Dementia AD : Not Pathogenic, FTD : Not Pathogenic Unknown. Unchanged Aβ42/Aβ40 ratio; unchanged Aβ42; No change in proteolytic products PSEN2-CTF and PSEN2-NTF.

rs58973334
Coding
Exon 4
Point, Missense
CGC to CAC
0 Cruts et al., 1998;
Gallo et al., 2010
P69A
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Unknown.

Coding
Exon 4
Point, Missense
CCC to GCC
0 Dobricic et al., 2012
R71W
Alzheimer's Disease, None, Parkinson's Disease Dementia AD : Not Pathogenic Leukoencephalopathy with periventricular white-matter lacunar infarctions. Unchanged Aβ42/Aβ40 ratio; Reduces the stability of the presenilin-2 protein and impairs Notch signaling.

rs140501902
Coding
Exon 4
Point, Missense
CGG to TGG
0 Sleegers et al., 2004
K82R
Alzheimer's Disease AD : Unclear Pathogenicity Unknown; neuroimaging showed diffuse cortical atrophy, especially in the posterior region and mild hippocampal atrophy. FDG-PET showed widespread hypometabolism. PIB-PET showed amyloid deposition in the frontal lobe, lateral temporal lobe, parietal lobe, posterior cingulate cortex, precuneus, and striatum.

 

Unknown.

Coding
Exon 4
Point, Missense
AAA to AGA
0 Shi et al., 2015
A85V
Alzheimer's Disease, Dementia with Lewy Bodies AD : Pathogenic, DLB : Unclear Pathogenicity Amyloid deposition; Neurofibrillary changes; Diffuse Lewy bodies in the neocortex; Bilateral basal ganglia calcifications. Unknown.

rs63750048
Coding
Exon 4
Point, Missense
GCG to GTG
0 Piscopo et al., 2008
V101M
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Unknown; predicted probably damaging in silico.

Coding
Exon 4
Point, Missense
GTG to ATG
0 Sala Frigerio et al., 2015
K115Efs*
Alzheimer's Disease AD : Pathogenic Unknown; FDG-PET showed hypometabolism in the parietal and temporal lobes. The deletion of two nucleotides from exon 5 leads to a frameshift and ultimately to a premature stop codon in exon 6. This is predicted to result in either a truncated presenilin-2 protein or transcript degradation due to nonsense-mediated decay.

Coding
Exon 4
Deletion
AAG to A--
0 Jayadev et al., 2010
T122P
Alzheimer's Disease AD : Pathogenic Unknown. Increased Aβ42/Aβ40 ratio; increased Aβ42; No change in proteolytic products PSEN2-CTF and PSEN2-NTF.

rs63749851
Coding
Exon 5
Point, Missense
ACG to CCG
0 Finckh et al., 2000
T122R
Atypical Dementia Atypical Dementia : Pathogenic Variable cortical and subcortical atrophy. Reduced calcium ion released from intracellular stores.

rs28936380
Coding
Exon 5
Point, Missense
ACG to AGG
0 Binetti et al., 2003
P123L
Alzheimer's Disease AD : Unclear Pathogenicity Unknown; Neuroimaging showed diffuse cortical atrophy, predominantly in the right hemisphere. FDG-PET showed hypoperfusion in the right temporal and parietal regions. Unknown; predicted probably damaging in silico.

Coding
Exon 5
Point, Missense
CCA to CTA
0 Xia et al., 2015
E126fs
Alzheimer's Disease AD : Unclear Pathogenicity Unknown; neuroimaging showed hippocampal and parahippocampal atrophy. Unknown; the insertion of one nucleotide (A) is predicted to result in a frameshift at codon 126.

Coding
Exon 5
Insertion
GAG.GAC to GAA.GGA
0 El Kadmiri et al., 2014
E126K
Alzheimer's Disease AD : Pathogenic Unknown. Unknown; predicted probably damaging in silico.

Coding
Exon 5
Point, Missense
GAG to AAG
0 Müller et al., 2014
S130L
Alzheimer's Disease, None, Parkinson's Disease Dementia AD : Unclear Pathogenicity Neuropathology consistent with AD at autopsy in at least one case. Unchanged Aβ42/Aβ40 ratio; unchanged Aβ42; No change in proteolytic products PSEN2-CTF and PSEN2-NTF.

rs63750197
Coding
Exon 5
Point, Missense
TCG to TTG
0 Sorbi et al., 2002;
Tedde et al., 2003
V139M
Alzheimer's Disease, None AD : Unclear Pathogenicity Bilateral hypoperfusion in the parietal-temporal lobes. Unknown.

Coding
Exon 5
Point, Missense
GTG to ATG
0 Bernardi et al., 2008
N141I
(Volga German)
Alzheimer's Disease AD : Pathogenic Extensive amyloid plaques; Extensive neurofibrillary tangles (typically a Braak score of V or VI); α-synuclein inclusions, especially in the amygdala; Rare TDP-43 pathology; Hippocampal sclerosis. Increased Aβ42/Aβ40 ratio; increased Aβ42; No change in proteolytic products PSEN2-CTF and PSEN2-NTF.

rs63750215
Coding
Exon 5
Point, Missense
AAC to ATC
5 Levy-Lahad et al., 1995;
Rogaev et al., 1995
N141Y
Alzheimer's Disease AD : Pathogenic Proband had autopsy-confirmed AD with severe brain atrophy and numerous plaques and neurofibrillary tangles. Unknown; predicted damaging in silico.

rs61761208
Coding
Exon 5
Point, Missense
AAC to TAC
0 Niu et al., 2014
L143H
None AD : Not Pathogenic Not applicable. Unknown.

Coding
Exon 5
Point, Missense
CTC to CAC
0 Guerreiro et al., 2010
V148I
Alzheimer's Disease AD : Pathogenic Unknown. Unchanged Aβ42/Aβ40 ratio; unchanged Aβ42; No change in proteolytic products PSEN2-CTF and PSEN2-NTF.

rs63750812
Coding
Exon 5
Point, Missense
GTC to ATC
0 Lao et al., 1998
K161R
Alzheimer's Disease AD : Pathogenic Unknown. Unknown.

Coding
Exon 5
Point, Missense
AAG to AGG
0 Wallon et al., 2012
R163H
None AD : Not Pathogenic Not applicable. Unknown.

Coding
Exon 5
Point, Missense
CGC to CAC
0 Puschmann et al., 2009
H169N
Alzheimer's Disease, Frontotemporal Dementia, Progressive Nonfluent Aphasia AD : Unclear Pathogenicity, FTD : Unclear Pathogenicity Unknown; neuroimaging showed mild atrophy and widespread hypometabolism. PIB-PET showed amyloid deposition in the AD case, but no amyloid deposition in the FTD case. Unknown.

Coding
Exon 6
Point, Missense
CAT to AAT
0 Shi et al., 2015
M174V
Alzheimer's Disease, Frontotemporal Dementia AD : Not Pathogenic Unknown; imaging has shown frontal atrophy and hypoperfusion in temporoparietal regions. Unknown; predicted benign in silico.

rs61757781
Coding
Exon 6
Point, Missense
ATG to GTG
0 Andreoli et al., 2008;
Clarimón et al., 2008;
Guerreiro et al., 2010
S175C
Alzheimer's Disease AD : Pathogenic Unknown; MRI showed focal atrophy in the medial temporal lobe; SPECT showed bilateral hypoperfusion in temporoparietal regions. Unknown.

Coding
Exon 6
Point, Missense
TCT to TGT
0 Piscopo et al., 2010
G212V
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD. Unknown; predicted pathogenic in silico.

Coding
Exon 7
Point, Missense
GGG to GTG
0 Marín-Muñoz et al., 2016
V214L
Alzheimer's Disease AD : Pathogenic Unknown; neuroimaging showed diffuse cortical atrophy and widespread hypometabolism. Unknown; structural changes were predicted in silico, especially at amino acids 214, 219, and 220. PolyPhen2 predicted a probably or possibly damaging effect.

Coding
Exon 7
Point, Missense
GTG to TTG
0 Youn et al., 2014
Q228L
Alzheimer's Disease AD : Pathogenic Unknown. Unknown.

rs63750880
Coding
Exon 7
Point, Missense
CAG to CTG
0 Zekanowski et al., 2003
Y231C
Frontotemporal Dementia FTD : Pathogenic Unknown; MRI showed diffuse subcortical and cortical atrophy, particularly in the frontotemporoparietal lobes. Unknown.

Coding
Exon 7
Point, Missense
TAC to TGC
0 Marcon et al., 2009
I235F
Alzheimer's Disease, None AD : Not Pathogenic Not applicable. Unknown.

Coding
Exon 7
Point, Missense
ATC to TTC
0 Lee et al., 2014
A237V
Alzheimer's Disease AD : Unclear Pathogenicity Neuropathology consistent with AD. Unknown; predicted possibly damaging in silico.

rs200670135
Coding
Exon 7
Point, Missense
GCG to GTG
0 Sassi et al., 2014
L238F
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Unknown; predicted probably damaging in silico.

Coding
Exon 7
Point, Missense
CTC to TTC
0 Sala Frigerio et al., 2015
L238P
Alzheimer's Disease AD : Pathogenic Unknown; MRI showed supratentorial cortical atrophy, particularly atrophy of the parietal cortex. Unknown; predicted damaging in silico.

Coding
Exon 8
Point, Missense
CTC to CCC
0 Blauwendraat et al., 2016
M239I
Alzheimer's Disease AD : Pathogenic Moderate cortical atrophy; Numerous neurofibrillary tangles; Numerous senile plaques, especially in the amygdala. Increased Aβ42/Aβ40 ratio; increased Aβ42; No change in proteolytic products PSEN2-CTF and PSEN2-NTF; Reduced calcium release.

rs63749884
Coding
Exon 7
Point, Missense
ATG to ATA
0 Finckh et al., 2000
M239V
Alzheimer's Disease AD : Pathogenic Diffuse cerebral atrophy; Senile plaques; Neurofibrillary tangles (stage VI of Braak and Braak); Ectopic neurons in the subcortical white matter; Extracellular "ghost" neurofibrillary tangles. Increased Aβ42/Aβ40 ratio; increased Aβ42; No change in proteolytic products PSEN2-CTF and PSEN2-NTF.

rs28936379
Coding
Exon 7
Point, Missense
ATG to GTG
0 Rogaev et al., 1995
A252T
None AD : Not Pathogenic Not applicable. Unknown.

rs138836272
Coding
Exon 7
Point, Missense
GCG to ACG
0 Guerreiro et al., 2010
A258T
None AD : Not Pathogenic Not applicable. Unknown.

rs148238688
Coding
Exon 7
Point, Missense
GCC to ACC
0 Sala Frigerio et al., 2015
T301M
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Unchanged Aβ42/Aβ40 ratio.

rs144277432
Coding
Exon 7
Point, Missense
ACG to ATG
0 Croes et al., 2004
K306fs
Alzheimer's Disease AD : Unclear Pathogenicity Unknown; neuroimaging showed cortical atrophy. Unknown; the deletion of a single nucleotide (A) in exon 9 is predicted to result in a frameshift at codon 306.

Coding
Exon 9
Deletion
AAG.CTG to AGC.TGG
0 El Kadmiri et al., 2014
P334A
Alzheimer's Disease, None AD : Not Pathogenic Not applicable. Unknown.

Coding
Exon 10
Point, Missense
CCT to GCT
0 Lee et al., 2014
P334R
Alzheimer's Disease, None AD : Not Pathogenic Not applicable. Unknown.

rs63750207
Coding
Exon 10
Point, Missense
CCT to CGT
0 Lleó et al., 2002
P348L
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Unknown.

Coding
Exon 10
Point, Missense
CCA to CTA
0 Blauwendraat et al., 2016
A377V
Alzheimer's Disease, None AD : Not Pathogenic Not applicable. Unknown.

Coding
Exon 11
Point, Missense
GCG to GTG
0 Lee et al., 2014
V393M
Alzheimer's Disease AD : Unclear Pathogenicity Unknown; bilateral hypometabolism in the parieto-occipital regions. Unchanged Aβ42/Aβ40 ratio; unchanged Aβ42.

rs142690225
Coding
Exon 11
Point, Missense
GTG to ATG
0 Lindquist et al., 2008
T430M
Alzheimer's Disease AD : Pathogenic Right frontotemporal hypoperfusion. Unknown.

rs63750666
Coding
Exon 12
Point, Missense
ACG to ATG
0 Ezquerra et al., 2003
D439A
Alzheimer's Disease AD : Unclear Pathogenicity Unknown; imaging showed moderate cortical atrophy in the frontal and parietal regions. Unchanged Aβ42/Aβ40 ratio; unchanged Aβ42; No change in proteolytic products PSEN2-CTF and PSEN2-NTF.

rs63750110
Coding
Exon 12
Point, Missense
GAC to GCC
0 Lleó et al., 2001

TREM2 (66)

TREM2 encodes Triggering Receptor Expressed on Myeloid Cells 2, a transmembrane receptor that modulates microglial activity and survival. TREM2 variants cause Nasu-Hakola disease (NHD), a rare autosomal recessive early-onset dementia, and may modify the risk of developing Alzheimer’s disease (AD), frontotemporal dementia (FTD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS).​

Mutation Clinical
Phenotype
Pathogenicity Neuropathology Biological Effect Genomic Position Genomic Region Mutation Type
Codon Change
Research
Models
Primary
Papers
E14X
Nasu-Hakola Disease NHD : Pathogenic Unknown. Premature truncation codon; no transcripts detected.

rs386834143
Coding
Exon 1
Point, Nonsense
GAG to TAG
0 Paloneva et al., 2003
S16F
AD : Unclear Pathogenicity Unknown. Unknown.

rs777808487
Coding
Exon 2
Point, Missense
TCC to TTC
0 Sirkis et al., 2016
G17E
AD : Unclear Pathogenicity, FTD : Unclear Pathogenicity Unknown. Predicted benign by Polyphen-2, tolerated by SIFT, neutral by SNPs&Go.

Coding
Exon 2
Point, Missense
GGA to GAA
0 Cuyvers et al., 2014
V27M
AD : Unclear Pathogenicity Unknown. Normal protein maturation in HEK293 cells.

rs768745050
Coding
Exon 2
Point, Missense
GTG to ATG
0 Sirkis et al., 2016
A28V
Primary Progressive Aphasia, Progressive Nonfluent Aphasia AD : Not Pathogenic, FTD : Unclear Pathogenicity Unknown. Normal protein maturation and increased cell-surface expression in HEK293 cells.

rs2234252
Coding
Exon 2
Point, Missense
GCG to GTG
0 Sims et al., 2017
S31F
AD : Unclear Pathogenicity Unknown. Normal protein maturation, decreased total and cell-surface expression in HEK293 cells.

rs746216516
Coding
Exon 2
Point, Missense
TCC to TTC
0 Sirkis et al., 2016
Q33X
Alzheimer's Disease, Frontotemporal Dementia, Nasu-Hakola Disease NHD : Pathogenic, FTD : Pathogenic, AD : Possible Risk Modifier Unknown for homozygous carriers; MRI showed cerebral atrophy. Heterozygous AD patient showed typical AD pathology. Loss of TREM2 expression.

rs104894002
Coding
Exon 2
Point, Nonsense
CAG to TAG
0 Soragna et al., 2003;
Guerreiro et al., 2013
Y38C
Frontotemporal Dementia FTD : Pathogenic Unknown; MRI shows cortical atrophy and white matter abnormalities. Alters post-translational processing of TREM2, ligand binding, and TREM2-mediated phagocytosis.

rs797044603
Coding
Exon 2
Point, Missense
TAT to TGT
1 Guerreiro et al., 2013
D39E
AD : Not Pathogenic, FTD : Unclear Pathogenicity Not applicable. Predicted to be possibly damaging by Polyphen-2, but to be tolerated by SIFT and neutral by SNPs&Go.

rs200392967
Coding
Exon 2
Point, Missense
GAC to GAG
0 Sims et al., 2017
D39G
AD : Unclear Pathogenicity, FTD : Unclear Pathogenicity Unknown. Predicted to be benign by Polyphen-2, tolerated by SIFT, and neutral by SNPs&Go.

Coding
Exon 2
Point, Missense
GAC to GGC
0 Cuyvers et al., 2014
H43Y
AD : Unclear Pathogenicity Unknown. Predicted benign by PolyPhen2.

Coding
Exon 2
Point, Missense
CAC to TAC
0 Pottier et al., 2013
W44X
Nasu-Hakola Disease NHD : Pathogenic Brain atrophy reported. Predicted to result in truncated protein lacking transmembrane and cytoplasmic domains.

rs104894001
Coding
Exon 2
Point, Nonsense
TGG to TGA
0 Paloneva et al., 2002
G45E
AD : Unclear Pathogenicity Unknown. Unknown.

Coding
Exon 2
Point, Missense
GGG to GAG
0 Jonsson et al., 2013
R47C
Behavioral variant FTD AD : Unclear Pathogenicity, FTD : Pathogenic Unknown, but MRI showed symmetric frontal and temporal lobe atrophy in homozygous carrier. Normal protein maturation, decreased total and cell-surface expression in HEK293 cells.

rs753325601
Coding
Exon 2
Point, Missense
CGC to TGC
0 Sirkis et al., 2016;
Ng et al., 2018
R47H
Alzheimer's Disease, Frontotemporal Dementia, Amyotrophic Lateral Sclerosis, Parkinson's Disease AD : Risk Modifier, FTD : Possible Risk Modifier, PD : Possible Risk Modifier, ALS : Possible Risk Modifier AD patients heterozygous for the R47H variant:  generally typical AD pathology, but subtle differences compared to non-carriers, including decreased microglial coverage of amyloid plaques and accumulation of phagosomes in microglia. Decreased ligand binding to TREM2 and impaired TREM2-mediated activation.

rs75932628
Coding
Exon 2
Point, Missense
CGC to CAC
19 Guerreiro et al., 2013;
Jonsson et al., 2013
W50C
Nasu-Hakola Disease NHD : Pathogenic Unknown; imaging showed brain atrophy, diffuse white-matter hyperintensities, thinning of the corpus callosum, and basal ganglia calcification. Unknown; predicted to be harmful in silico by Polyphen-2 and SIFT.

Coding
Exon 2
Point, Missense
GAG to TAG
0 Dardiotis et al., 2017
R52H
AD : Unclear Pathogenicity Unknown. Lower cell-surface expression than wild-type TREM2 when co-expressed with its adaptor protein DAP12 in a reporter cell line, but activation by phospholipids similar in cells expressing R52H and wild-type TREM2.

rs374851046
Coding
Exon 2
Point, Missense
CGC to CAC
0 Jin et al., 2014
G58A
AD : Unclear Pathogenicity, FTD : Unclear Pathogenicity Unknown. Predicted by Polyphen2 to be probably damaging, by SIFT to be tolerated, and by SNPs&Go to be neutral.

Coding
Exon 2
Point, Missense
GGC to GCC
0 Cuyvers et al., 2014
R62C
AD : Unclear Pathogenicity Unknown. Lower cell-surface expression than wild-type TREM2 when co-expressed with its adaptor protein DAP12 in a reporter cell line; activation by lipid ligands reduced in cells expressing R62C compared with cells expressing wild-type TREM2.

rs201258314
Coding
Exon 2
Point, Missense
CGT to TGT
0 Pottier et al., 2013;
Song et al., 2017
R62H
Alzheimer's Disease AD : Risk Modifier AD patients heterozygous for the R62H variant: decreased microglial coverage of amyloid plaques and increased accumulation of phagosomes in microglia, compared to non-carriers. Decreased ligand binding to TREM2 and impaired TREM2-mediated activation.

rs143332484
Coding
Exon 2
Point, Missense
CGT to CAT
0 Jin et al., 2014;
Sims et al., 2017
T66M
Behavioral variant FTD FTD : Pathogenic Unknown; MRI showed frontal lobe atrophy, ventricular enlargement, and white-matter abnormalities in one homozygous carrier, and frontal and parietal lobe atrophy in two other homozygous carriers. Greatly decreased cell-surface expression and shedding of sTREM2, reduced ligand binding, and impaired phagocytosis.

rs201258663
Coding
Exon 2
Point, Missense
ACG to ATG
1 Guerreiro et al., 2013
N68K
AD : Unclear Pathogenicity Unknown. Predicted  benign by PolyPhen2; apparently normal protein folding.

rs753372932
Coding
Exon 2
Point, Missense
AAC to AAG
0 Guerreiro et al., 2013
L72V
AD : Unclear Pathogenicity Unknown. Predicted by SIFT to be tolerated but by Polyphen2 to be damaging.

rs765933093
Coding
Exon 2
Point, Missense
CTG to GTG
0 Ghani et al., 2016
W78X
Nasu-Hakola Disease NHD : Pathogenic Brain atrophy has been reported. Predicted to result in truncated protein lacking transmembrane and cytoplasmic domains.

rs104893998
Coding
Exon 2
Point, Nonsense
TGG to TAG
0 Paloneva et al., 2002
D86V
Frontotemporal Dementia FTD : Unclear Pathogenicity Unknown; MRI of a patient carrying both the Y38C and D86V variants, showed cortical atrophy, thinning of the corpus callosum, periventricular white-matter abnormalities,ventricular enlargement and probable globus pallidus calcification. Decreased cell-surface expression and defective N-linked glycosylation.

Coding
Exon 2
Point, Missense
GAC to GTC
0 Guerreiro et al., 2013
D87N
Alzheimer's Disease AD : Possible Risk Modifier Typical AD pathology in single described case (Braak Stage 6). Decreased binding to lipoproteins in cell-free assay, but increased ligand-stimulated activation in reporter cell line.

rs142232675
Coding
Exon 2
Point, Missense
GAT to AAT
0 Guerreiro et al., 2013
G90VfsX99
(TREM2 269delG)
Nasu-Hakola Disease NHD : Pathogenic Unknown; MRI showed leukoencephalopathy and cerebral atrophy. Unknown.

rs386834140
Coding
Exon 2
Deletion
GGT to GTG
0 Klünemann et al., 2005
T96K
Frontotemporal Dementia FTD : Possible Risk Modifier Unknown; carriers of the T96K/W191X/L211P variants have lower levels of sTREM2 in CSF, compared with noncarriers. Increased binding to cell-derived ligands and increased activation by phospholipids seen in reporter cell line.

rs2234253
Coding
Exon 2
Point, Missense
ACG to AAG
0 Thelen et al., 2014
R98W
AD : Unclear Pathogenicity, FTD : Unclear Pathogenicity Unknown. Predicted to be probably damaging by PolyPhen2.

rs147564421
Coding
Exon 2
Point, Missense
CGG to TGG
0 Guerreiro et al., 2013
A105RfsX84
(TREM2 313delG)
Nasu-Hakola Disease NHD : Pathogenic Unknown; imaging showed cerebral atrophy, leukoencephalopathy, thinning of the corpus callosum, basal ganglia calcification. Unknown.

rs386834141
Coding
Exon 2
Deletion
GCG to CGG
0 Klünemann et al., 2005
A105T
Primary Progressive Aphasia, Semantic Dementia FTD : Unclear Pathogenicity Unknown. Predicted to be neutral by SIFT and by the PolyPhen 2 HumVar algorithm, but to be possibly damaging by PolyPhen2 HumDiv.

Coding
Exon 2
Point, Missense
GCG to ACG
0 Thelen et al., 2014
A105V
AD : Not Pathogenic Unknown. Unknown.

rs145080901
Coding
Exon 2
Point, Missense
GCG to GTG
0 Sims et al., 2017;
Jin et al., 2015
S116C
AD : Unclear Pathogenicity, FTD : Unclear Pathogenicity Unknown. Cell-surface expression similar to that of wild-type TREM2 heterologously expressed in HEK293 cells.

Coding
Exon 2
Point, Missense
AGT to TGT
0 Borroni et al., 2014
V126G
Nasu-Hakola Disease NHD : Pathogenic Unknown; MRI showed leukoencephalopathy with sparing of arcuate fibers, cerebral atrophy, and thinning of the corpus callosum. Poor cell-surface expression and defective for N-linked glycosylation in the Golgi.

rs121908402
Coding
Exon 2
Point, Missense
GTG to GGG
0 Klünemann et al., 2005
A130S
AD : Unclear Pathogenicity Unknown. Normal protein maturation when heterologously expressed in HEK293 cells.

Coding
Exon 2
Point, Missense
GCA to TCA
0 Sirkis et al., 2016
A130V
AD : Unclear Pathogenicity Unknown. Predicted by SIFT to be damaging.

rs201280312
Coding
Exon 2
Point, Missense
GCA to GTA
0 Jiao et al., 2014
D131D
AD : Not Pathogenic Not applicable. Unknown.

rs139607688
Coding
Exon 3
Point, Silent
GAC to GAT
0 Sims et al., 2017
L133L
AD : Unclear Pathogenicity, FTD : Unclear Pathogenicity Unknown. Unknown.

rs144250872
Coding
Exon 3
Point, Silent
CTG to CTT
0 Cuyvers et al., 2014
D134G
Frontotemporal Dementia, Nasu-Hakola Disease NHD : Pathogenic, FTD : Unclear Pathogenicity Brain atrophy. Unknown.

rs28939079
Coding
Exon 3
Point, Missense
GAT to GGT
0 Paloneva et al., 2002
R136Q
Logopenic Progressive Aphasia AD : Not Pathogenic, FTD : Unclear Pathogenicity Unknown. Normal protein maturation, slightly reduced cell-surface expression in HEK293 cells.

rs149622783
Coding
Exon 3
Point, Missense
CGG to CAG
0 Sims et al., 2017
R136W
AD : Unclear Pathogenicity Unknown. Normal protein maturation, decreased total and cell-surface expression in HEK 293 cells; when stimulated by phospholipids, reporter cells expressing the R136W variant responded similarly to cells expressing wild-type TREM2.

rs772641807
Coding
Exon 3
Point, Missense
CGG to TGG
0 Jin et al., 2014
E151K
AD : Not Pathogenic Unknown. Normal protein maturation but reduction in overall expression in HEK 293 cells; when stimulated by phospholipids, reporter cells expressing the E151K variant responded similarly to cells expressing wild-type TREM2.

rs79011726
Coding
Exon 3
Point, Missense
GAG to AAG
0 Jonsson et al., 2013;
Sims et al., 2017
H157Y
Alzheimer's Disease AD : Possible Risk Modifier Unknown. Increases shedding of sTREM2. Reduces activation in response to phospholipid ligands and decreases phagocytosis.

rs2234255
Coding
Exon 3
Point, Missense
CAC to TAC
0 Jiang et al., 2016;
Jiang et al., 2016;
Sims et al., 2017
S162R
AD : Unclear Pathogenicity, FTD : Unclear Pathogenicity Unknown. Normal protein maturation in HEK293 cells.

rs371702633
Coding
Exon 4
Point, Missense
AGC to AGG
0 Cuyvers et al., 2014;
Sirkis et al., 2016
S183C
AD : Unclear Pathogenicity Unknown. Predicted to be possibly damaging by PolyPhen2.

rs200820365
Coding
Exon 4 of transcript variant 2
Point, Missense
AGC to TGC
0 Jiang et al., 2016
K186N
Nasu-Hakola Disease NHD : Pathogenic Brain atrophy. Predicted to result in defects in signal transduction.

 

 


rs28937876
Coding
Exon 4
Point, Missense
AAG to AAT
0 Paloneva et al., 2002
W191X
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Unknown.

rs2234258
Coding
Exon 4 of transcript variant 2
Point, Nonsense
TGG to TAG
0 Jin et al., 2015
A192T
AD : Not Pathogenic Unknown. Predicted to be possibly damaging by Polyphen2.

rs150277350
Coding
Exon 4
Point, Missense
GCC to ACC
0 Sims et al., 2017;
Jiang et al., 2016
A196T
AD : Unclear Pathogenicity Unknown. Unknown.

Coding
Exon 4
Point, Missense
GCA to ACA
0 Sirkis et al., 2016
W198X
Behavioral variant FTD FTD : Pathogenic Unknown; frontal lobe atrophy seen on MRI. Premature truncation.

Coding
Exon 4
Point, Nonsense
TGG to TGA
0 Giraldo et al., 2013
W200C
AD : Unclear Pathogenicity Unknown. Predicted to be probably damaging by Polyphen2.

Coding
Exon 4 of transcript variant 2
Point, Missense
TGG to TGC
0 Jiang et al., 2016
E202D
AD : Unclear Pathogenicity Unknown. Unknown.

rs530314472
Coding
Exon 4 of transcript variant 2
Point, Missense
GAG to GAT
0 Jin et al., 2014;
Jin et al., 2015
L205P
AD : Unclear Pathogenicity Unknown. Predicted by SIFT to be damaging, but by Polyphen2 to be benign.

Coding
Exon 4 of transcript variant 2
Point, Missense
CTG to CCG
0 Ghani et al., 2016
L211P
Alzheimer's Disease, Frontotemporal Dementia AD : Possible Risk Modifier, FTD : Possible Risk Modifier Unknown; lower levels of sTREM2 in CSF of T96K/W191X/L211P carriers. Predicted tolerated in silico by SIFT and benign by PolyPhen-2.

rs2234256
Coding
Exon 4
Point, Missense
CTG to CCG
0 Jin et al., 2015
H215Q
AD : Unclear Pathogenicity Unknown. Unknown.

Coding
Exon 4
Point, Missense
CAT to CAG
0 Jin et al., 2014
G219C
AD : Unclear Pathogenicity Unknown. Predicted by SIFT to be damaging but by Polyphen2 to be benign.

rs768583708
Coding
Exon 4 of transcript variant 2
Point, Missense
GGT to TGT
0 Ghani et al., 2016
T223I
AD : Not Pathogenic, FTD : Unclear Pathogenicity Unknown. Predicted by Polyphen2 to be benign, by SIFT to be tolerated and by SNPs&Go to be neutral; normal protein maturation in HEK293 cells.

rs138355759
Coding
Exon 4
Point, Missense
ACT to ATT
0 Sims et al., 2017
c.40+3 delAGG
Frontotemporal Dementia FTD : Pathogenic Unknown; MRI showed brain atrophy, including thinning of the corpus callosum. Reduction in the level of TREM2 transcripts.

Non-Coding
Intron 1
Deletion
0 Chouery et al., 2008
c.391+1G>A
Frontotemporal Dementia FTD : Pathogenic Magnetic resonance imaging revealed cortical atrophy, ventricular enlargement, pronounced thinning of the corpus callosum, and diffuse white-matter hyperintensites. Calcification of the globus pallidus was observed by computed tomography. In heterologous expression systems, this variant was found to cause abnormal splicing (i.e., retention of intron 2). Although TREM2 protein levels were not assayed in these in vitro studies, the lack of soluble TREM2 in the proband’s CSF suggests abnormal protein expression or processing.

Non-Coding
Intron 2
Point
0 Li et al., 2019
c.482+1G>A
Progressive Nonfluent Aphasia FTD : Pathogenic Unknown; MRI showed periventricular white-matter hyperintensities, enlargement of the lateral ventricles, and thinning of the corpus callosum. Unknown.

Non-Coding
Intron 3
Point
0 Chee et al., 2017
c.482+2T>C
Frontotemporal Dementia, Nasu-Hakola Disease NHD : Pathogenic, FTD : Unclear Pathogenicity Unknown; imaging showed brain atrophy, basal ganglia calcification, and hypoperfusion in the frontotemporal cortex of NHD patient. Exon 3 skipping, with deletion of exons 2 and/or 4, and the presence of premature or original stop codons; two truncated TREM2 protein products detected, which are likely to be nonfunctional.

rs386834144
Non-Coding
Intron 3
Point
0 Paloneva et al., 2002;
Numasawa et al., 2011
rs2234258
AD : Unclear Pathogenicity, FTD : Unclear Pathogenicity Unknown. Unknown.

rs2234258
Non-Coding
3' UTR
Point
0 Cuyvers et al., 2014
rs7748513
Alzheimer's Disease AD : Possible Risk Modifier Unknown. Unknown.

rs7748513
Non-Coding
Intron 2
Point
0 Reitz et al., 2013
rs7748777
Alzheimer's Disease, ~ 1 year follow-up AD : Possible Risk Modifier Unknown. Unknown.

rs7748777
Non-Coding
Upstream
Point
0 Wang et al., 2015
rs7759295
AD : Unclear Pathogenicity This variant was associated with a higher burden of neurofibrillary tangles in subjects from three prospective cohort studies, but not with amyloid plaques, amyloid angiopathy, Lewy body pathology, terminally activated microglia, or cerebral infarcts. Unknown.

rs7759295
Non-Coding
Upstream
Point
0 Replogle et al., 2015
rs9357347
Alzheimer's Disease AD : Possible Risk Modifier Unknown. Predicted to influence transcription factor binding; 6 percent increase in expression of TREM2 and TREML1 in temporal cortex.

rs9357347
Non-Coding
Intergenic - TREM locus
Point
0 Carrasquillo et al., 2017