Mutations

PSEN-1

PSEN1 encodes presenilin-1, a subunit of γ-secretase, the aspartyl protease responsible for Aβ generation. More than 300 mutations in PSEN1 have been reported and mutations in PSEN1 are the most common cause of early onset Alzheimer's disease.

Search Results

PSEN1 (309)

Mutation Clinical
Phenotype
Pathogenicity Neuropathology Biological Effect Genomic Position Genomic Region Mutation Type
Codon Change
Research
Models
Primary
Papers
Q15H
Frontotemporal Dementia FTD : Unclear Pathogenicity Unknown Unknown

1330528266
Coding
Exon 3
Point, Missense
CAG to CAC
0 Koriath et al., 2018
N32N
Alzheimer's Disease, None AD : Unclear Pathogenicity Unknown. Unknown.

Coding
Exon 4
Point, Silent
AAT to AAC
0 Scacchi et al., 2007
R35Q
None, Alzheimer's Disease AD : Unclear Pathogenicity Not applicable. In vitro, decreased Aβ40 and Aβ42 production; moderate increase in the Aβ42/aβ40 ratio.

rs63750592
Coding
Exon 4
Point, Missense
CGG to CAG
0 Rogaeva et al., 2001
N39Y
Alzheimer's Disease AD : Unclear Pathogenicity Unknown Unknown

Coding
Exon 4
Point, Missense
AAC to TAC
0 Koriath et al., 2018
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. Abrogated Aβ40 production and decreased Aβ42 production in vitro. 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. Decreased Aβ42 production and undetectable Aβ40 production in vitro. Does not cause a frame-shift.

Coding
Exon 4
Deletion
ACG to ---
0 Nicolas et al., 2015
R42L
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Unknown.

3677775281
Coding
Exon 4
Point, Missense
CGG to CTG
0 Koriath et al., 2018
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 in cells. Undetectable production of Aβ40 and drastically reduced production of Aβ42 in vitro.

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. In vitro, it reduced both Aβ40 and Aβ42 production, with very little effect on the Aβ42/Aβ40 ratio. 

rs63749967
Coding
Exon 4
Point, Missense
GTG to CTG
0 Campion et al., 1995
I83_M84del
(DelIM, ΔI83/M84, ΔI83/ΔM84)
Spastic Paraparesis, Alzheimer's Disease 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. In vitro, Aβ40 production is undetectable and Aβ42 production greatly reduced.

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
M84T
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD. Severe CAA, no Lewy bodies observed. Unknown.

Coding
Exon 4
Point, Missense
ATG to ACG
0 Lanoiselée et al., 2017
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
Myoclonus, Spastic Paraparesis, Parkinsonism, Alzheimer's Disease, Corticobasal Syndrome AD : Pathogenic, Corticobasal Syndrome : 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 in transfected cells. In vitro, decreased Aβ42 production and abrogated Aβ40 production.

rs63750599
Coding
Exon 4
Point, Missense
CTC to CCC
0 Ataka et al., 2004
P88H
Alzheimer's Disease AD : Pathogenic Unknown Unknown

Coding
Exon 4
Point, Missense
CCT to CAT
0 Lanoiselée et al., 2017
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>C)
Alzheimer's Disease AD : Pathogenic Typical Alzheimer's disease pathology. In vitro, decreased production of Aβ40 and Aβ42; increased Aβ42/Aβ40 ratio. In silico, 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
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. Decreased Aβ40 and Aβ42 production; increased Aβ42/Aβ40 ratio in vitro.

rs63750815
Coding
Exon 4
Point, Missense
GTG to TTG
0 Queralt et al., 2002
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. In vitro, abolished Aβ40 production and drastically reduced Aβ42 production.

rs63751141
Coding
Exon 4
Point, Missense
TGC to TCC
0 Tedde et al., 2003
V94M
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Decreased Aβ42 and Aβ40 production, but unchanged Aβ42/Aβ40 ratio, in vitro.

rs63750831
Coding
Exon 4
Point, Missense
GTG to ATG
0 Arango et al., 2001
V96F
Alzheimer's Disease AD : Pathogenic Unknown. In vitro, decreased Aβ42 and Aβ40 production; decreased autoproteolytic endopeptidase activity. In cultured cells, increased Aβ42/Aβ40 ratio. In silico, classified as damaging (PolyPhen) or tolerated (SIFT).

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. In vitro, slight decrease in Aβ42 and Aβ40 production.

rs63750852
Coding
Exon 4
Point, Missense
GTG to TTG
0 Jia et al., 2005
T99A
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Decreased Aβ42, and particularly Aβ40, production resulting in increased Aβ42/Aβ40 ratio in vitro.

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. Decreased Aβ42, and particularly Aβ40, production in vitro, resulting in increased Aβ42/Aβ40 ratio.

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. Decreased Aβ42 production and undetectable Aβ40 production in vitro.

rs200646139
Coding
Exon 4
Point, Missense
CGG to CAG
0 Dobricic et al., 2012
G111V
Alzheimer's Disease AD : Pathogenic Unknown, but an MRI scan of one case revealed bilateral hippocampal atrophy. Reduced Aβ40, unchanged Aβ42, and elevated Aβ42/Aβ40 ratio in transfected cells. In silico analyses (PANTHER, Mutation Taster, and PolyPhen-2) predict probably pathogenic. 

Coding
Exon 4
Point, Missense
GGG to GTG
0 Qiu et al., 2019
G111W
Alzheimer's Disease AD : Pathogenic Unknown Unknown

Coding
Exon 4
Point, Missense
GGG to TGG
0 Lanoiselée et al., 2017
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. Decreased Aβ40 production in vitro; increased Aβ42/Aβ40 ratio.  

rs63751399
Coding
Exon 4
Point, Missense
CTA to CAA
0 Finckh et al., 2005
Y115C
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD. Increased Aβ42:Aβ40 ratio in cells and in vitro. In cells, increased Aβ42 secretion; in vitro, decreased Aβ42, and especially Aβ40, production. Also, disruption of lysosome function and autophagy via accumulation of APP β-C-terminal fragments.

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, but MRI and FDG-PET showed atrophy and hypometabolism in temporal and parietal regions. Unknown, but predicted to be damaging and disruptive of 3D conformation by several in silico analyses (PolyPhen2, PROVEAN, ExPASY, Raptor X).

rs63750730
Coding
Exon 5
Point, Missense
ACC to ATC
0 La Bella et al., 2004
T116S; P117T
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD in biopsies from two individuals.  Unknown. In silico predictions mixed: deleterious (PolyPhen2, SIFT, PROVEAN); uncertain significance (Mutation Taster 2); medium effect (Mutation Assessor); T116S neutral and P117T pathogenic (PredictSNP).

Coding
Exon 5
Insertion/Deletion
ACC CCA to TCT ACA
0 Blanco et al., 2019
T116N
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD. Decreased Aβ40 and Aβ42 production; increased Aβ42/Aβ40 ratio in vitro.

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. 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
P117Q
Alzheimer's Disease AD : Pathogenic Unknown, but CSF biomarkers (Aβ42, tau, and phospho-tau) were in the AD pathological range in one case. Unknown

Coding
Exon 5
Point, Missense
CCA to CAA
0 Lanoiselée et al., 2017
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
T119I
Alzheimer's Disease AD : Pathogenic Unknown, but in one case, PiB-PET revealed amyloid deposition in frontal, parietal, precuneus/posterior cingulate, lateral temporal, and striatal regions, and PET-FDG showed hypometabolism in the parietal lobe, precuneus, anterior cingulate, dorsal frontal lobe, and lateral temporal lobe. CSF Aβ42 was reduced in one case and CSF phospho-tau elevated in another. Unknown, but in silico analyses predict it to be damaging or possibly damaging (PolyPhen2); damaging or tolerated (SIFT), and neutral (Provean). CADD-PHRED score = 24.

Coding
Exon 5
Point, Missense
ACA to ATA
0 Itzcovich et al., 2019;
Giau et al., 2019
E120D (A>C)
Alzheimer's Disease AD : Pathogenic Unknown. Decreased Aβ42, and particularly Aβ40, production in vitro, resulting in an increased Aβ42/Aβ40 ratio.

rs63751272
Coding
Exon 5
Point, Missense
GAA to GAC
0 Poorkaj et al., 1998
E120D (A>T)
Alzheimer's Disease AD : Pathogenic Unknown. Decreased Aβ42, and particularly Aβ40, production in vitro, resulting in increased Aβ42/Aβ40 ratio.    

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.
 

Decreased Aβ38 and Aβ40 production and Aβ38/Aβ42 ratio in patient brain sample. Increased Aβ42/Aβ40 in cells. Predicted probably damaging in silico.

Coding
Exon 5
Point, Missense
GAA to GGA
0 Lladó et al., 2009;
Gómez-Tortosa et al., 2010
E120K
Nasu-Hakola Disease, Spastic Paraparesis, Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD. Increased Aβ42/Aβ total ratio and extracellular Aβ in cells; reduced Aβ40 and Aβ42 production in vitro; increased Aβ42/Aβ40 ratio in vitro.

rs63750800
Coding
Exon 5
Point, Missense
GAA to AAA
0 Hutton et al., 1996
T122A
Frontotemporal Dementia FTD : Pathogenic Unknown Unknown

Coding
Exon 5
Point, Missense
ACC to GCC
0 Koriath et al., 2018
E123K
Alzheimer's Disease AD : Pathogenic Unknown, but in 2 cases, MRI showed atrophy in the medial temporal lobes, and PET showed hypoperfusion in the temporal and parietal lobes. Decreased Aβ40 and Aβ42 production, and an elevated Aβ42/Aβ40 ratio in vitro. Mutation site not conserved between PSEN1 and PSEN2

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. Decreased Aβ40 and Aβ42 production in vitro, with slight increase in Aβ42/Aβ40 ratio.  

Coding
Exon 5
Point, Missense
CAC to CGC
0 Ikeda et al., 2013
S132A
Dementia with Lewy Bodies, Myoclonus AD : Pathogenic, DLB : Pathogenic Neuropathology consistent with AD, with severe neocortical Lewy body disease (one case). Unknown, but in silico algorithms predict the mutation to be probably damaging by Polyphen and “neutral” by Provean. Site is conserved between PSENs.

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. Decreased Aβ42, and abrogated Aβ40, production in vitro. 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 and in vitro; increases intracellular and secreted Aβ42 and decreases Aβ40 in cells; reduces both Aβ42 and Aβ40 production in vitro.

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
A137T
Frontotemporal Dementia FTD : Pathogenic Unknown Unknown

Coding
Exon 5
Point, Missense
GCC to ACC
0 Koriath et al., 2018
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/Aβ40 ratio and decreased Aβ38/Aβ42 ratio in in vitro assay using patient brain samples. Increased Aβ42/Aβ total ratio in transfected cells.  

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 Alzheimer's Disease Collaborative Group, 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
V142I
Alzheimer's Disease AD : Pathogenic Unknown Unknown

rs63751037
Coding
Exon 5
Point, Missense
GTC to ATC
0 Koriath 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 residue forming part of the APP-binding pore.  

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, but other mutations at this location alter Aβ peptide production and, in wild-type PSEN1, I143 forms part of the substrate-binding pore.  

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
Myoclonus, Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD. Increased Aβ42/Aβ40 ratio. Increased Aβ42 and decreased Aβ40 secretion in cells; decreased Aβ42 and Aβ40 production in vitro.

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 and Aβ42/Aβ40 ratio in cells and in vitro.

Coding
Exon 5
Point, Missense
ATT to GTT
0 Gallo et al., 2011
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. Also, disrupted lysosome function and autophagy seemingly due to accumulation of β-C-terminal APP fragments.

rs63750391
Coding
Exon 5
Point, Missense
ATG to ATT
0 Rogaeva et al., 2001
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. Also, disrupted lysosome function and autophagy seemingly due to accumulation of β-C-terminal APP fragments. 

rs63750391
Coding
Exon 5
Point, Missense
ATG to ATC
0 Gustafson et al., 1998
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. Also, disrupted lysosome function and autophagy seemingly due to accumulation of β-C-terminal APP fragments.

rs63750391
Coding
Exon 5
Point, Missense
ATG to ATA
0 Jørgensen et al., 1996;
Janssen et al., 2003
M146L (A>C)
Pick's disease, Alzheimer'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
14 Sherrington et al., 1995;
Sorbi et al., 1995;
Alzheimer's Disease Collaborative Group, 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 and Aβ43; 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. Disrupts endosomes via accumulation of APP β-CTF.

rs63750306
Coding
Exon 5
Point, Missense
ATG to GTG
6 Alzheimer's Disease Collaborative Group, 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. Decreased Aβ42 production and abrogated Aβ40 production in vitro.

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
Spastic Paraparesis, Alzheimer's Disease AD : Pathogenic Unknown, MRI and SPECT showed atrophy and hypoperfusion in occipito-parietal areas and internal temporal lobe areas, including the hippocampus. Dramatically decreased Aβ40 and Aβ42 production, as well as decreased endopeptidase activity, 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
Y159F
Alzheimer's Disease AD : Pathogenic Unknown, but CSF biomarkers suggestive of AD. Unknown.

rs778630379
Coding
Exon 5
Point, Missense
TAT to TTT
0 Kerchner and Holbrook, 2012
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
Myoclonus, Alzheimer's Disease 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 Alzheimer's Disease Collaborative Group, 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>T)
Alzheimer's Disease AD : Pathogenic Unknown, MRI showed diffuse cerebral and cerebellar atrophy in one case. Unknown, but in silico analyses (SIFT and polyphen) predict the mutation is deleterious, probably damaging.

Coding
Exon 6
Point, Missense
TGG to TGT
0 Syama et al., 2018
W165C (G>C)
Alzheimer's Disease AD : Pathogenic Unknown

rs63741484
Coding
Exon 6
Point, Missense
TGG to TGC
0 Campion et al., 1999
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
Spastic Paraparesis, Alzheimer's Disease 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. Disrupts endosomes via accumulation of APP β-CTF. 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. Decreased Aβ42 production and undetectable production of Aβ40 in vitro. Predicted pathogenic in silico.

Coding
Exon 6
Deletion
TTA to ---
0 Jiao et al., 2014
I167del (TATdel)
Alzheimer's Disease AD : Pathogenic Unknown Decreased Aβ42 production and undetectable production of Aβ40 in vitro. Predicted pathogenic in silico.

rs63750879
Coding
Exon 6
Deletion
ATT.ATA to ATA
0 Janssen et al., 2003
I168T
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD. Decreased Aβ42 production and abrogated Aβ40 production in vitro; 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. Decreased Aβ42 and abrogation of Aβ40 production in vitro. No effect on Notch.

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, but cryo-EM analysis of the γ-secretase-complex revealed a direct interaction of the wild-type residue with APP.

rs63751210
Coding
Exon 6
Point, Missense
TCA to TTA
0 Taddei et al., 1998
S169P
Myoclonic seizure, Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD, including numerous plaques and neurofibrillary tangles, neuritic irregularities, neuronal lipofuscin, and mild astrocytosis. Increased Aβ42 and moderately decreased Aβ40 production in vitro; increased Aβ42/Aβ40.

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. Increased Aβ42/Aβ40 ratio in cells and in vitro, but effects on Aβ42 and Aβ40 levels varied between studies.  

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 Unknown Drastically decreased Aβ42 production and Aβ40 production was undetectable in vitro.

rs63750963
Coding
Exon 6
Point, Missense
CTA to CCA
0 Ramirez-Dueñas et al., 1998
L173F (G>T)
Alzheimer's Disease AD : Pathogenic Unknown. Unknown. 

Coding
Exon 6
Point, Missense
TTG to TTT
0 Jin et al., 2012
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
L173S
Alzheimer's Disease AD : Pathogenic Unknown Unknown, predicted to be damaging by 4 in silico analyses. PHRED-CADD score=24.1

Coding
Exon 6
Point, Missense
TTG to TCG
0 Wang et al., 2019
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
F175del
Myoclonic seizure, Alzheimer's Disease AD : Pathogenic Unknown, but MRI and FDG-PET observations, as well as CSF biomarkers, were consistent with AD. Increased Aβ42 and Aβ39; decreased Aβ40 in cultured cells.

Coding
Exon 6
Deletion
TTC to ---
0 Vöglein et al., 2019
F175S
Late-onset AD : Unclear Pathogenicity 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. Abrogates Aβ40 production and dramatically reduces Aβ42 production in vitro.

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 Dramatically reduced production of Aβ42 and abrogated production of Aβ40 in vitro.

rs63750155
Coding
Exon 6
Point, Missense
TCA to CCA
0 Rogaeva et al., 2001
I180N
Alzheimer's Disease AD : Pathogenic Unknown Unknown

Coding
Exon 6
Point, Missense
ATT to AAT
0 Lanoiselée et al., 2017
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. Increase in Aβ42/Aβ40 ratio in cells and in vitro; reduced production of Aβ40 and Aβ42 in vitro. No effect on Notch cleavage. Generates alternative transcripts coding for truncated proteins, possibly causing loss of function. Forms complexes with wild-type PSEN1, possibly suppressing activity.

rs63751068
Coding
Exon 6
Point, Missense
GGG to GTG
0 Dermaut et al., 2004
E184D
Alzheimer's Disease AD : Pathogenic, DLB : Pathogenic, PPA : Pathogenic Neuropathology consistent with AD in three cases. In addition, CAA pathology described in two cases. Also, in two cases, robust Lewy body pathology and, in one of these cases, accumulation of the non-Aβ component of AD amyloid (NAC) in plaques and astrocytes. Decreased Aβ40 and Aβ42 production, and increased Aβ42:Aβ40 ratio, as assessed in vitro.

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, CAA : Pathogenic Neuropathology was consistent with AD, with severe CAA, in one case. CAA included included chronic inflammatory infiltrate surrounding some cortical and leptomeningeal blood vessels. Lewy pathology was found in the amygdala.  Decreased Aβ40 and Aβ42 production in vitro. In patient brain membranes, reduced Aβ38 production and Aβ38/Aβ42 ratio; increased Aβ42/Aβ40 ratio.  

Coding
Exon 7
Point, Missense
ATC to TTC
0 Church et al., 2011
W203C
Amyotrophic Lateral Sclerosis ALS : Unclear Pathogenicity Unknown Unknown. In silico analyses predict it to be deleterious (SIFT, PolyPhen2, and Mutation Taster).

1384308168
Coding
Exon 7
Point, Missense
TGG to TGC
0 Couthouis et al., 2014
F205_G206del;insC
Alzheimer's Disease AD : Pathogenic Unknown Unknown

Coding
Exon 7
Deletion
TTTGGT to T---GT
0 Lanoiselée et al., 2017
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. Increased Aβ42 production; reduced interaction with Pen2; disrupted ER calcium homeostasis.

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. Decreased Aβ40 and Aβ42 production; increased Aβ42/Aβ40 ratio in vitro.

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, but in silico analyses predicted it to be deleterious.

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 by PolyPhen2, SIFT, and Provean.

Coding
Exon 7
Point, Missense
GGA to GCA
0 An et al., 2016
G209E
Alzheimer's Disease AD : Pathogenic Unknown, but MRI revealed global cerebral atrophy, particularly affecting the hippocampus. FDG-PET showed global hypometabolism, particularly affecting the temporal, parietal, and occipital lobes. 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. Abrogated Aβ40 production and drastically reduce Aβ42 production in vitro.

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. Abrogated Aβ40 production and drastically reduced Aβ42 production in vitro.

rs63750053
Coding
Exon 7
Point, Missense
GGA to GTA
0 Poorkaj et al., 1998
M210R
Alzheimer's Disease AD : Pathogenic Unknown, but levels of AD biomarkers in proband's CSF (Aβ42, tau, phospho-tau) were in the pathological range. Unknown.

Coding
Exon 7
Point, Missense
ATG to AGG
0 Lanoiselée et al., 2017
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. Increased Aβ40, Aβ42, and the Aβ42/Aβ40 ratio in cells; dramatically decreased Aβ42 and abrogated Aβ40 production in vitro.

Coding
Exon 7
Point, Missense
TCC to TAC
0 Ringman et al., 2011
I213F
Alzheimer's Disease AD : Pathogenic Unknown Increased Aβ40 and Aβ42 secretion, and increased Aβ42/Aβ40 ratio in transfected cells.

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.   Decreased short (Aβ38, Aβ40, and Aβ42), and increased long (Aβ43, Aβ45, Aβ46+) Aβ peptides in cell lysates and knockin mouse brains. Increased Aβ42/Aβ40 ratio, and decreased Aβ38/Aβ42 and Aβ40/Aβ43 ratios.   

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
H214R
Alzheimer's Disease AD : Pathogenic Unknown, but in one case, MRI showed mild white matter demyelination of the frontal and parietal lobes, with no apparent atrophy of the cerebral cortex or hippocampus. Unknown, but six in silico algorithms predicted it is deleterious.

Coding
Exon 7
Point, Missense
CAC to CGC
0 Li et al., 2019
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
Parkinsonism, Alzheimer's Disease AD : Pathogenic Cotton wool plaques in the cortex, caudate nucleus, putamen, claustrum, thalamus, substantia innominate, and colliculi. Unknown.

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. Increased Aβ42/Aβ40 ratio in cells and in vitro. Decreased production of Aβ40 and Aβ42 in vitro. 

Coding
Exon 7
Point, Missense
GGT to CGT
0 Norton et al., 2009
L219F
Alzheimer's Disease AD : Pathogenic Unknown Decreased Aβ40; increased Aβ42 and the Aβ42/Aβ40 ratio in vitro.

rs63749987
Coding
Exon 7
Point, Missense
CTT to TTT
0 Terreni et al., 2016
L219P
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD in one case; meningeal CAA in cortex and cerebellum. PET and SPECT show hypoperfusion and hypometabolism in temporal lobes and right parietal lobe. Unknown

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, but predicted to be probably damaging by Polyphen and deleterious by Provean. Conserved between species and PSENs; other pathogenic mutations at this site.

Coding
Exon 7
Point, Missense
CAG to CCG
0 Scahill et al., 2013;
Ryan et al., 2016
Q222R
Alzheimer's Disease AD : Pathogenic Unknown Increased Aβ40 and Aβ42 production, as well as the Aβ42/Aβ40 ratio in vitro.

rs63750009
Coding
Exon 7
Point, Missense
CAG to CGG
0 Rogaeva et al., 2001
Q223R
Alzheimer's Disease, Spastic Paraparesis AD : Pathogenic Unknown, but cotton-wool plaques and neurofibrillary tangles were found in two biopsies of family members of a mutation carrier. MRI of mutation carrier revealed white matter lesions in the frontotemporal region. FDG-PET showed progressive decrease in glucose metabolism in the precuneus and posterior cingulate, with parietal regions affected later.  Decreased CSF Aβ42 in two cases. In cells, decreased Aβ40 levels (decreased Aβ43 cleavage), and increased Aβ42 levels (decreased Aβ42 cleavage). In vitro, nearly complete ablation of Aβ40 and Aβ42 production.  

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
I227V
Alzheimer's Disease AD : Pathogenic Unknown Unknown

rs199842082
Coding
Exon 7
Point, Missense
ATT to GTT
0 Koriath et al., 2018
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. Drastically decreased Aβ42 production and abrogated Aβ40 production in vitro.

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, but atomic structure indicates wild-type residue directly interacts with APP substrate.

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>C)
Alzheimer's Disease AD : Pathogenic Unknown; imaging showed global cerebral atrophy. In vitro, increased Aβ42 production, decreased Aβ40 production; increased Aβ42:Aβ40 ratio. In cells, increased Aβ42 and Aβ43, decreased total Aβ production, increased Aβ42:Aβ40 ratio. Disrupts endosomes via accumulation of APP β-CTF.

rs63751287
Coding
Exon 7
Point, Missense
ATG to CTG
0 Aldudo et al., 1999
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. Increased Aβ42 and decreased Aβ40 production, resulting in increased Aβ42/Aβ40 ratio in vitro. In cells, increased Aβ42/Aβ40 ratio, decreased total Aβ production and elevated levels of Aβ42 and Aβ43. Also, poromotes accumulation of APP β-CTFs which disrupt endosomes.

rs63751287
Coding
Exon 7
Point, Missense
ATG to TTG
0 Mendez and McMurtray, 2006
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
Myoclonus, Alzheimer's Disease 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. Drastically decreased Aβ42 production and abrogated Aβ40 production in vitro. Expression 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. Drastically decreased Aβ42 production and abrogated Aβ40 production in vitro. Also, caused incomplete endoproteolytic processing of PSEN1. 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. Decreased Aβ40 and Aβ42 production in vitro, without changing the Aβ42/Aβ40 ratio. Elevated monoamine-oxidase-A activity.

rs63751130
Coding
Exon 7
Point, Missense
CTG to GTG
0 Janssen et al., 2003
F237C
Alzheimer's Disease AD : Pathogenic Unknown Unknown. Evolutionarily conserved codon across species and between human PSEN1 and PSEN2.

Coding
Exon 7
Point, Missense
TTT to TGT
0 Lanoiselée et al., 2017
F237I
Spastic Paraparesis, Alzheimer's Disease AD : Pathogenic Unknown, but in proband, PET and SPECT revealed hypometabolism and hypoperfusion in bilateral temporoparietal areas, including primary and sensory motor cortices. Decreased production of Aβ42 and Aβ40 in vitro, but Aβ42/Aβ40 ratio similar to wild-type.

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. Increased Aβ40, Aβ42, and the Aβ42/Aβ40 ratio when expressed in HEK293 cells expressing APP with the Swedish mutation. In vitro, abrogated production of both Aβ40 and Aβ42.

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
L241R
Alzheimer's Disease AD : Pathogenic Unknown, but mutation carrier had CSF AD biomarker levels (Aβ42, tau, phospho-tau) in the pathological range.  Unknown

Coding
Exon 7
Point, Missense
CTC to CGC
0 Lanoiselée et al., 2017
P242Lfs
(P242LfsX11)
Familial Acne Inversa Familial Acne Inversa : Pathogenic Not applicable. Decreases PSEN1 mRNA due to premature stop codon, nonsense-mediated decay. No effect on APP cleavage, but enhances Notch signaling. Also enhances cytokine and chemokine expression, and prolongs TNF-α production in monocytes and macrophages. 

Coding
Exon 7
Deletion
CCT to CTG
0
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 and Aβ43 secretion, Aβ42/Aβ40 ratio, Aβ42/Aβ total ratio. Decreased production of Aβ40 and Aβ42 in vitro. Disrupts endosomes via accumulation of APP β-CTF. 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
I249L
Amyotrophic Lateral Sclerosis, Alzheimer's Disease ALS : Unclear Pathogenicity, AD : Pathogenic Unknown, but MRI from one case revealed hippocampal and cortical atrophy. Increased Aβ42 and Aβ42/Aβ40 ratio, with no effect on PSEN1 endoproteolysis or Aβ43 production, in transfected cells. In silico analyses yielded mixed results: SIFT=tolerated; PolyPhen2=possibly damaging; Mutation Taster=disease causing.

rs1363575880
Coding
Exon 7
Point, Missense
ATC to CTC
0 Couthouis et al., 2014
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
Y256N
Alzheimer's Disease AD : Pathogenic Unknown, but MRI revealed temporal lobe and hippocampal atrophy in one case. Unknown, but in silico algorithms predict the mutation is deleterious.

Coding
Exon 7
Point, Missense
TAT to AAT
0 Li et al., 2019
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
Spastic Paraparesis, Alzheimer's Disease AD : Pathogenic, SP : Pathogenic, CAA : Pathogenic Neuropathology consistent with AD, with cotton-wool plaques, CAA, and degeneration of spinal lateral pyramidal tracts. Decreased Aβ42 and Aβ40 production, and increased Aβ42/Aβ40 ratio 5-fold in vitro. Also, abolished autoproteolysis in vitro.

rs63750964
Coding
Exon 8
Point, Missense
GTT to TTT
0 Rogaeva et al., 2001;
Farlow et al., 2000;
Farlow et al., 2001
V261I
Alzheimer's Disease AD : Pathogenic Consistent with AD, with widespread cotton wool plaques. Unknown.

Coding
Exon 8
Point, Missense
GTT to ATT
0 Miravalle et al., 2005
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
L262S
Alzheimer's Disease AD : Pathogenic Unknown Predicted to be damaging by four different algorithms, with a PHRED-CADD score of 32.

Coding
Exon 8
Point, Missense
TTG to TCG
0 Wang et al., 2019
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 Neuropathology consistent with AD. Decreased Aβ40 and Aβ42 production and increased Aβ42/Aβ40 ratio in vitro.

rs63750543
Coding
Exon 8
Point, Missense
TGT to CGT
0 Wasco et al., 1995
P264L
Spastic Paraparesis, Alzheimer's Disease, Atypical Dementia, Progressive Nonfluent Aphasia 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. Increased Aβ42/Aβ40 and decreased Aβ38/Aβ42 ratios; increased Aβ42, and decreased Aβ40 and Aβ38 production; Deposition of PSEN-1 in the endoplasmic reticulum; impaired mitochondrial activity and ATP production.

rs63750301
Coding
Exon 8
Point, Missense
CCG to CTG
1 Campion et al., 1995;
Wasco et al., 1995
G266S
Spastic Paraparesis, Alzheimer's Disease, Cerebral Amyloid Angiopathy 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 Alzheimer's Disease Collaborative Group, 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, CAA : Pathogenic Neuropathology consistent with Alzheimer's disease; a high burden of Aβ and neurofibrillary tangles in cortical areas. Prominent microbleeds in the cerebellum, parieto-occipital region, and temporal lobe revealed by MRI in one patient. MRI in two cases showed white matter alterations. 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. In vitro, Aβ40 and Aβ42 production were abrogated, but in cells, increased Aβ42 secretion was reported, with no change in Aβ production.
 


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
V272D
Alzheimer's Disease AD : Pathogenic Unknown, but MRI in one case revealed frontotemporal atrophy. Increased Aβ42/Aβ40 ratio in cultured cells. 

Coding
Exon 8
Point, Missense
GTT to GAT
0 Mengel et al., 2019
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. Moderately decreased Aβ40 production and increased Aβ42/Aβ40 ratio in vitro.

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
Spastic Paraparesis, Alzheimer's Disease 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
Spastic Paraparesis, Alzheimer's Disease AD : Pathogenic Unknown Unknown

rs63750524
Coding
Exon 8
Point, Missense
AGA to AGC
0 Raman et al., 2007
R278T
Spastic Paraparesis, Alzheimer's Disease 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 Alzheimer's Disease Collaborative Group, 1995;
Lopera et al., 1997;
Lemere et al., 1996
E280G
Spastic Paraparesis, Alzheimer's Disease 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 Alzheimer's Disease Collaborative Group, 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. Decreased Aβ42 and obliterated Aβ40 production in vitro.

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. In vitro, Aβ42 and Aβ40 production, as well as Aβ42/Aβ40 ratio, similar to wild-type. Impairs trafficking of the APOE receptor apoER2.

rs63749937
Coding
Exon 8
Point, Missense
CTT to GTT
0 Dermaut et al., 2001
F283L
Alzheimer's Disease, Corticobasal Syndrome AD : 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 Cotton wool plaques and severe amyloid angiopathy (2 cases); brain hematoma at early age (3 cases). Decreased Aβ37, Aβ38, Aβ39, and Aβ42 in patient CSF; increased Aβ15 and Aβ20. Increased Aβ42/43 amyloid production in cultured cells; reduced production rates of Aβ38 and Aβ40 in isolated brain membranes, and decreased Aβ38/Aβ42 ratio.

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
11 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, but in silico analyses predicted it to be possibly damaging (PoyPhen) and neutral (Provean). 

Coding
Exon 9
Point, Missense
ACA to GCA
0 Ryan et al., 2016
T291P
Spastic Paraparesis, Alzheimer's Disease AD : Pathogenic Unknown; MRI showed marked diffuse atrophy and a signal in the right temporal lobe, compatible with previous bleeding. In cells, this mutation increased both Aβ40 and Aβ42, causing an overall increase in the Aβ42/Aβ40 ratio. However, in an in vitro assay, it dramatically decreased Aβ42 and abolished Aβ40 production. Also affects exon 9 splicing.

rs63750298
Coding
Exon 8
Point, Missense
ACA to CCA
0 Dumanchin et al., 2006
P303L
Frontotemporal Dementia FTD : Unclear Pathogenicity Unknown. Unknown.

rs147638016
Coding
Exon 9
Point, Missense
CCG to CTG
0 Koriath et al., 2018
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. Slight decrease of Aβ42 and Aβ40 production, with Aβ42/Aβ40 ratio similar to wildtype as assessed in vitro.

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 the mutant increased the Aβ42:Aβ40 ratio, but markedly reduced the levels of both secreted Aβ40 and Aβ42. In vitro, production of Aβ42 was markedly decreased and production of Aβ40 was abolished.

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, but brain imaging showed generalized atrophy in one case and cortical parieto-temporal hypometabolism in another. CSF levels of Aβ42, total tau, and phospho-tau were consistent with AD in the latter case.  Decreased Aβ42 and Aβ40 production, and decreased Aβ42/Aβ40 ratio in vitro. Decreased Aβ42 in CSF of one case.

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

rs63751174
Coding
Exon 10
Point, Missense
CGA to CAA
0 Rogaeva et al., 2001
A360T
Alzheimer's Disease AD : Pathogenic Unknown. In mutation carrier, CSF Aβ42 was reduced, but tau and phospho-tau levels were normal Unknown

rs199715992
Coding
Exon 10
Point, Missense
GCT to ACT
0 Lanoiselée et al., 2017
S365A
Alzheimer's Disease AD : Unclear Pathogenicity Unknown In vitro production of Aβ38, Aβ40, Aβ42, and Aβ43 similar to wildtype in one study; in another Aβ40 and Aβ42 production moderately increased, with Aβ42/Aβ40 ratio unchanged. Another study reported 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. In vitro, decreased Aβ42 production and abrogated Aβ40 production.

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. Decreased Aβ42 and abrogation of Aβ40 production in vitro. Predicted to have a damaging effect by SIFT, Polyphen, and Mutation Taster.

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
Spastic Paraparesis, Alzheimer's Disease 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 and Aβ42+; decreased Aβ40, Aβ38, Aβ38/Aβ42, and Aβ40/Aβ43. Blocks activity of ER calcium leak channel.

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
F386L
Alzheimer's Disease AD : Pathogenic Unknown. Unknown, but predicted to be pathogenic by in silico analyses (SIFT and PolyPhen2).

rs1555358095
Coding
Exon 11
Point, Missense
TTC to TCA
0 Yagi et al., 2014
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 Unknown Unknown

rs63750218
Coding
Exon 11
Point, Missense
CTG to CCG
0 Tedde et al., 2000
L392V
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD, including cortical atrophy, amyloid plaques, and neurofibrillary tangles. Increased Aβ42:Aβ40 ratio; increased Aβ48-39 production line, including Aβ42, in cells; decreased Aβ40 production in vitro. Impaired Notch cleavage. 

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
V393F
Alzheimer's Disease AD : Pathogenic Unknown Unknown, but predicted deleterious by in silico analysis (CADD Phred score= 35).

Coding
Exon 11
Point, Missense
GTT to TTT
0 Koriath et al., 2018
G394V
Alzheimer's Disease AD : Pathogenic Unknown In vitro, Aβ40 production undetectable; Aβ42 drastically reduced; autoproteolysis abrogated. Four algorithms predicted the mutation to be damaging, with a PHRED-CADD score of 31. 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 Neuropathology was consistent with AD, plus widespread α-synuclein inclusions characteristic of Lewy body disease, in one case. MRI of another case 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 Neuropathology consistent with AD. Decreased Aβ40 and Aβ42 production, and decreased Aβ42/Aβ40 ratio in vitro.

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 : Unclear Pathogenicity 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
G417A
Alzheimer's Disease, Parkinsonism AD : Pathogenic Unknown, but MRI and PET are consistent with AD in one case. PiB-PET showed diffuse amyloid in the cerebellum, and the frontal, parietal, and temporal cortices. Unknown, but in silico analyses predict mutation is damaging (PolyPhen2, SIFT, Provean). Changes in amino acid bulkiness, polarity, and hydrophobicity, together with 3D modeling, suggest reduced flexibility in transmembrane helix. Splicing may also be affected.

Coding
Exon 12
Point, Missense
GGT to GCT
0 Giau et al., 2018
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. Decreased Aβ40 and Aβ42 production; increased Aβ42/Aβ40 ratio in vitro.

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
L424P
Alzheimer's Disease AD : Pathogenic Unknown, but in proband, MRI showed medial temporal lobe atrophy and global cortical atrophy; PET showed hypometabolism in parietal areas, the precuneus, and the posterior cingulate cortex. Also, reduced CSF Aβ42. Unknown, but predicted pathogenic by in silico algorithms (MutationTaster, PolyPhen, Provean, and SIFT). 3D in silico analysis predicted shortening of two intramembrane α-helices and creation of a new one.

Coding
Exon 12
Point, Missense
CTC to CCC
0 Guven et al., 2019
L424R
Alzheimer's Disease, Spastic Paraparesis AD : Pathogenic Unknown; MRI showed cortical and subcortical atrophy with a thin corpus callosum. Unknown, MRI showed cortical and subcortical atrophy with a thin corpus callosum.

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. Increased Aβ40, Aβ42, and Aβ42/Aβ40 in vitro.

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 Unknown, but in one case FDG-PET at MCI-AD stage showed low metabolic rates in posterior cingulate gyrus, posterior and lateral parietal cortices, and medial temporal regions; elevated tau and phospho-tau in CSF. Unknown. At MCI-AD stage, normal CSF Aβ42 levels

rs63750083
Both
Exon 12
Point, Missense
GCA to GTA
0 Matsushita et al., 2002
P433S
Alzheimer's Disease AD : Pathogenic Unknown Increased Aβ42, Aβ43, and Aβ42/Aβ40 ratio in transfected cells. Reduced PSEN1 endoproteolysis.

Coding
Exon 12
Point, Missense
CCA to TCA
0 Koriath et al., 2018
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. Increased Aβ42 and decreased Aβ40 production in vitro, resulting in an increased Aβ42/Aβ40 ratio.

rs63750528, rs63750341
Coding
Exon 12
Point, Double
GCT to TGT
0 Devi et al., 2000
A434T
Parkinsonism, 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 PDD : Pathogenic, AD : Pathogenic Cotton-wool plaques, Lewy bodies, CAA, neuronal loss in cortex and substantia nigra, corticospinal tract degeneration in one case. Abrogation of Aβ40 production and dramatic reduction of Aβ42 production in vitro. Near abrogation of autoproteolysis.

rs63750470
Coding
Exon 12
Deletion
ACC to ---
0 Ishikawa et al., 2005
869-1G>A
Alzheimer's Disease AD : Pathogenic Unknown Unknown, but predicted to disrupt splicing.

Non-Coding
Intron 8/11
Point
0 Koriath et al., 2018
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 in intron 8 upstream of exon 9, resulting in exon 9 skipping. Decreased short (Aβ38, Aβ40) and increased long (Aβ42+) Aβ peptides; increased Aβ42/Aβ40 in vitro, cells, and mouse brain. Disrupted several cellular functions.

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
L171_ L172insY
(Leu171Tyr)
Alzheimer's Disease AD : Pathogenic Unknown Unknown

Coding
Exon 6
Insertion/Deletion
0 Koriath et al., 2018
S290C;T291_S319del
(ΔE9Finn, Δ9Finn, Δ9)
Spastic Paraparesis, Alzheimer's Disease 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. 4.6 kb deletion including entire exon 9 and extending into flanking intronic sequences; results in skipping of exon 9 and S290C substitution at the splice junction of exons 8 and 10. Decreased short (Aβ38, Aβ40) and increased long (Aβ42+) Aβ peptides; increased Aβ42/Aβ40 in vitro, cells, and mouse brain. Disrupted several cellular functions.

Both
Intron 8, Exon 9
Complex
0 Crook et al., 1998;
Prihar et al., 1999
S290C;T291_S319del
(ΔE9, Δ9)
Spastic Paraparesis, Alzheimer's Disease 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. 5.9 kb deletion including entire exon 9 and extending into flanking intronic sequences; results in skipping of exon 9 and S290C substitution at the splice junction of exons 8 and 10. Decreased short (Aβ38, Aβ40) and increased long (Aβ42+) Aβ peptides; increased Aβ42/Aβ40 in vitro, cells, and mouse brain. Disrupted several cellular functions.

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 splice acceptor site in intron 8 resulting in skipping of exon 9 and S290C change at the splice junction of exons 8 and 10. Decreased short (Aβ38, Aβ40) and increased long (Aβ42+) Aβ peptides; increased Aβ42/Aβ40 in vitro, cells, and mouse brain. Disrupted several cellular functions.

Both
Intron 8, Exon 9
Complex
0 Rovelet-Lecrux et al., 2015
S290C;T291_S319del G>A
(ΔE9, Δ9)
Spastic Paraparesis, Alzheimer's Disease AD : Pathogenic Cotton-wool plaques are common, in addition to classic neuritic, amyloid plaques. Tangles, neuronal loss, atrophy typical of AD. Point mutation in splice acceptor site in intron 8 resulting in skipping of exon 9 and S290C change at the splice junction of exons 8 and 10. Decreased short (Aβ38, Aβ40) and increased long (Aβ42+) Aβ peptides; increased Aβ42/Aβ40 in vitro, cells, and mouse brain. Disrupted several cellular functions.

rs63750219
Both
Intron 8, Exon 9
Complex
0 Sato et al., 1998
S290C;T291_S319del G>T
(ΔE9, Δ9)
Spastic Paraparesis, Alzheimer's Disease 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 S290C change at the splice junction of exon 8 and 10. Decreased short (Aβ38, Aβ40) and increased long (Aβ42+) Aβ peptides; increased Aβ42/Aβ40 in vitro, cells, and mouse brain. Disrupted several cellular functions.

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;
Lanoiselée et al., 2017