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PSEN1 (252)

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

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

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

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

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

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

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

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

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

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

Coding
Exon 4
Point, Missense
ATC to ACC
0 Achouri-Rassas et al., 2015
M84V
Alzheimer's Disease, Spastic Paraparesis AD : Pathogenic Unknown, but MRI showed cortical and cerebellar atrophy. Unknown, predicted to be possibly damaging by PolyPhen and to be disease-causing by MutationTaster.

Coding
Exon 4
Point, Missense
ATG to GTG
0 Gallo et al., 2017
L85P
Alzheimer's Disease, Spastic Paraparesis AD : Pathogenic Neuropathological examination was not available. SPECT and PET showed bilateral hypoperfusion and hypometabolism in the occipital and temporal lobes. Increased Aβ42/Aβ40 ratio; increased Aβ42.

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

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

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

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

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

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

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

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

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

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

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

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

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

rs200646139
Coding
Exon 4
Point, Missense
CGG to CAG
0 Dobricic et al., 2012
L113_I114insT
(Intron4, InsTAC, p.113+1delG, splice5)
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD, including considerable neuronal loss in the hippocampus and entorhinal cortex and numerous neuritic plaques and neurofibrillary tangles in the hippocampus. Deletion of a single nucleotide (G) in splice donor consensus site of intron 4 produces three aberrant transcripts: 1) a single codon insertion (TAC); 2) partial deletion of exon 4; and 3) complete deletion of exon 4. The latter two transcripts have frame shifts and premature stop codons.

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

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

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

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

rs63749962
Coding
Exon 5
Point, Missense
TAT to GAT
0
Y115H
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD. Increased Aβ42/Aβ40 ratio; increased Aβ42; decreased intracelluar Aβ40

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

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

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

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

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

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

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

rs63750550
Coding
Exon 5
Point, Missense
CCA to TCA
0 Dowjat et al., 2004
E120D (A>T)
Alzheimer's Disease AD : Pathogenic Unknown. Unknown.

rs63751272
Coding
Exon 5
Point, Missense
GAA to GAT
0 Reznik-Wolf et al., 1996
E120D (A>C)
Alzheimer's Disease AD : Pathogenic Unknown. Unknown.

rs63751272
Coding
Exon 5
Point, Missense
GAA to GAC
0 Poorkaj et al., 1998
E120G
Alzheimer's Disease AD : Pathogenic

Frequent amyloid plaques and neurofibrillary tangles; Severe amyloid angiopathy.
 

Unknown; predicted probably damaging in silico.

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

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

rs63750378
Coding
Exon 5
Point, Missense
GAG to AAG
0 Yasuda et al., 1999
H131R
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Unknown.

Coding
Exon 5
Point, Missense
CAC to CGC
0 Ikeda et al., 2013
L134R
Alzheimer's Disease AD : Pathogenic Unknown; MRI of the Turkish proband showed atrophy of the cerebrum and cerebellum. Unknown; predicted probably damaging in silico.

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

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

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

Coding
Exon 5
Point, Missense
AAT to TAT
0 Natelson Love et al., 2017
A136G
Alzheimer's Disease AD : Pathogenic

rs41345849
Coding
Exon 5
Point, Missense
GCT to GGT
0 Fang and Jia, 2007
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
M139T
Alzheimer's Disease AD : Pathogenic Unknown. Increased Aβ42/Aβ total ratio.

rs63751106
Coding
Exon 5
Point, Missense
ATG to ACG
0 Campion et al., 1995
M139V
Alzheimer's Disease, Atypical Dementia AD : Pathogenic Neuropathology consistent with AD. Increased Aβ42/Aβ40 ratio.

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

Coding
Exon 5
Point, Missense
GTC to TTC
0 Wang et al., 2018
I143F
Alzheimer's Disease AD : Pathogenic

rs63750322
Coding
Exon 5
Point, Missense
ATT to TTT
0 Rossor et al., 1996;
Palmer et al., 1999
I143M
Alzheimer's Disease AD : Pathogenic

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

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

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

Coding
Exon 5
Point, Missense
ATT to GTT
0 Gallo et al., 2011
M146I (G>C)
Alzheimer's Disease AD : Pathogenic

rs63750391
Coding
Exon 5
Point, Missense
ATG to ATC
0 Gustafson et al., 1998
M146I (G>T)
Alzheimer's Disease AD : Pathogenic

rs63750391
Coding
Exon 5
Point, Missense
ATG to ATT
0 Rogaeva et al., 2001
M146I (G>A)
Alzheimer's Disease AD : Pathogenic

rs63750391
Coding
Exon 5
Point, Missense
ATG to ATA
0 Jørgensen et al., 1996
M146L (A>T)
Alzheimer's Disease AD : Pathogenic

rs63750306
Coding
Exon 5
Point, Missense
ATG to TTG
0 Morelli et al., 1998
M146L (A>C)
Alzheimer's Disease, Pick's disease AD : Pathogenic Neuropathology consistent with AD in multiple affected mutation carriers. Pick bodies also have been noted in some cases. Increased Aβ42/Aβ total ratio; increased Aβ42/Aβ40 ratio; increased Aβ42.

rs63750306
Coding
Exon 5
Point, Missense
ATG to CTG
10 Sherrington et al., 1995;
Sorbi et al., 1995;
, 1995
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; Inhibits store-operated calcium channel activity.

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

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

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

Coding
Exon 6
Point, Missense
CTG to CCG
0 Wallon et al., 2012
L153V
Alzheimer's Disease AD : Pathogenic

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

rs63751292
Coding
Exon 5
Point, Missense
TAT to TGT
0 Janssen et al., 2003
Y154N
Alzheimer's Disease, Spastic Paraparesis AD : Pathogenic

rs63750588
Coding
Exon 5
Point, Missense
TAT to AAT
0 Hattori et al., 2004
K155_Y156insFI
(InsFI)
Alzheimer's Disease, Spastic Paraparesis AD : Pathogenic

rs63750631
Coding
Exon 5
Insertion
TAC to TTT.ATA.TAC
0 Rogaeva et al., 2001;
Moretti et al., 2004
H163P
Alzheimer's Disease AD : Unclear Pathogenicity Brain biopsy of the frontal cortex showed numerous senile plaques and neurofibrillary tangles compatible with a diagnosis of AD. No spongiform changes or abnormal prion proteins were detected. Increased Aβ42/Aβ40 ratio; increased Aβ42; decreased Aβ40.

Coding
Exon 5
Point, Missense
CAT to CCT
0 Kim et al., 2012
H163R
Alzheimer's Disease, Myoclonus AD : Pathogenic Data are limited, but neuropathology consistent with AD has been observed in at least one case. Increased Aβ42/Aβ total ratio in COS-1 cells; 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 Unknown; decreased glucose metabolism in presymptomatic mutation carriers, especially in the thalamus. Increased Aβ42/Aβ total ratio when expressed in COS-1 cells co-transfected with APP695.

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

Coding
Exon 6
Point, Missense
GCC to GTC
0 Roeber et al., 2015
W165C
Alzheimer's Disease AD : Pathogenic

rs63741484
Coding
Exon 6
Point, Missense
TGG to TGC
0 Campion et al., 1999
W165G
Alzheimer's Disease AD : Pathogenic

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

rs63750265
Coding
Exon 6
Point, Missense
CTT to CAT
0 Pantieri et al., 2005
L166P
Alzheimer's Disease, Spastic Paraparesis AD : Pathogenic Numerous Aβ-positive neuritic and cotton-wool plaques throughout the cerebral cortex; Abundant Aβ-positive amyloid cores in the cerebellar cortex. Increased Aβ42/Aβ ratio; Reduced cleavage of Notch and N-cadherin.

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
Alzheimer's Disease AD : Pathogenic Unknown. Unknown; predicted pathogenic in silico.

Coding
Exon 6
Deletion
TTA to ---
0 Jiao et al., 2014
I168del
Alzheimer's Disease AD : Pathogenic

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

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

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

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

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

rs63750577
Coding
Exon 6
Point, Missense
TCT to TTT
0 Snider et al., 2005
L171P
Alzheimer's Disease AD : Pathogenic

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
L173W
Alzheimer's Disease AD : Pathogenic Unknown. Unknown.

rs63750299
Coding
Exon 6
Point, Missense
TTG to TGG
0 Campion et al., 1999
L174M
Alzheimer's Disease AD : Pathogenic

rs63751144
Coding
Exon 6
Point, Missense
CTG to ATG
0 Bertoli Avella et al., 2002;
Sorbi et al., 2002
L174R
Alzheimer's Disease AD : Pathogenic

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

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

Coding
Exon 6
Point, Missense
TTT to CTT
0 Müller et al., 2013
F177L
Alzheimer's Disease AD : Pathogenic

rs63749911
Coding
Exon 6
Point, Missense
TTT to CTT
0 Rogaeva et al., 2001
F177S
Alzheimer's Disease AD : Pathogenic

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

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

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

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

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

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

Coding
Exon 7
Point, Missense
ATC to TTC
0 Church et al., 2011
G206A
Alzheimer's Disease AD : Pathogenic Typical AD neuropathology, including extensive plaques and tangles (Braak stage VI). Increased Aβ42; unchanged Aβ40.

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

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

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

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

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

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

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

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

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

rs63750861
Coding
Exon 7
Point, Missense
ATT to TTT
0 Zekanowski et al., 2003
I213T
Alzheimer's Disease AD : Pathogenic Unknown. Unknown.

rs63751039
Coding
Exon 7
Point, Missense
ATT to ACT
0 Kamino et al., 1996
H214D
Alzheimer's Disease AD : Pathogenic

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

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

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

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

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

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

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

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

Coding
Exon 7
Point, Missense
CGA to CCA
0 Piccoli et al., 2016
Q222H
Alzheimer's Disease AD : Pathogenic

rs63751072
Coding
Exon 7
Point, Missense
CAG to CAC
0 Miklossy et al., 2003
Q222R
Alzheimer's Disease AD : Pathogenic

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

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

rs63750487
Coding
Exon 7
Point, Missense
CTC to TTC
0 Zekanowski et al., 2006
L226R
Alzheimer's Disease AD : Pathogenic

rs63749961
Coding
Exon 7
Point, Missense
CTC to CGC
0 Coleman et al., 2004
I229F
Alzheimer's Disease AD : Pathogenic

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

Coding
Exon 7
Point, Missense
AGT to ATT
0 Wallon et al., 2012
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

rs63749836
Coding
Exon 7
Point, Missense
GCC to ACC
0 Campion et al., 1995
A231V
Alzheimer's Disease AD : Pathogenic

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>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
M233I (G>A)
Alzheimer's Disease AD : Pathogenic Unknown. Unknown.

Coding
Exon 7
Point, Missense
ATG to ATA
0 Wallon et al., 2012
M233L (A>T)
Alzheimer's Disease FTD : Pathogenic

rs63751287
Coding
Exon 7
Point, Missense
ATG to TTG
0 Mendez and McMurtray, 2006
M233L (A>C)
Alzheimer's Disease AD : Pathogenic Unknown; imaging showed global cerebral atrophy. Unknown.

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

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

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

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

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

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

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

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

Coding
Exon 7
Point, Missense
ATC to ATG
0 Ting et al., 2014
K239N
Alzheimer's Disease AD : Pathogenic

Coding
Exon 7
Point, Missense
AAG to AAC
0 Lladó et al., 2010
T245P
Alzheimer's Disease AD : Pathogenic

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/Aβ total ratio.

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

Coding
Exon 7
Point, Missense
CTC to CGC
0 Clarimón et al., 2008;
Guerreiro et al., 2010
L250S
Alzheimer's Disease AD : Pathogenic

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

rs63750634
Coding
Exon 7
Point, Missense
TTG to GTG
0 Furuya et al., 2003
Y256S
Alzheimer's Disease AD : Pathogenic

rs63751320
Coding
Exon 7
Point, Missense
TAT to TCT
0 Miklossy et al., 2003
A260V
Alzheimer's Disease AD : Pathogenic

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

rs63750964
Coding
Exon 8
Point, Missense
GTT to TTT
0 Rogaeva et al., 2001;
Farlow et al., 2000;
Farlow et al., 2001
V261L
Alzheimer's Disease, Spastic Paraparesis AD : Pathogenic

Coding
Exon 8
Point, Missense
GTT to CTT
0 Jiménez Caballero et al., 2008
L262F
Alzheimer's Disease AD : Pathogenic

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

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

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

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

rs63750301
Coding
Exon 8
Point, Missense
CCG to CTG
1 Campion et al., 1995;
Wasco et al., 1995
G266S
Alzheimer's Disease, Cerebral Amyloid Angiopathy, Spastic Paraparesis AD : Pathogenic, CAA : Pathogenic

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

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

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

rs63751229
Coding
Exon 8
Point, Missense
CCA to TCA
0 , 1995;
Hutton et al., 1996
R269G
Alzheimer's Disease, Myoclonus AD : Pathogenic

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

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

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


rs63750886
Coding
Exon 8
Point, Missense
CTG to GTG
0 Kwok et al., 2003
V272A
Alzheimer's Disease, Parkinsonism, Subcortical Dementia AD : Pathogenic

rs63750680
Coding
Exon 8
Point, Missense
GTT to GCT
0 Jimenez-Escrig et al., 2004
E273A
Alzheimer's Disease AD : Pathogenic

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

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

Coding
Exon 8
Point, Missense
GCT to GTT
0 Luedecke et al., 2014
R278I
Alzheimer's Disease, Progressive Nonfluent Aphasia AD : Pathogenic, Progressive Nonfluent Aphasia : Pathogenic Unknown; MRI showed multiple white-matter foci; Atrophy minimal or absent. Selective increase in secreted Aβ43; Impaired endoproteolysis of presenilin-1.

rs63749891
Coding
Exon 8
Point, Missense
AGA to ATA
1 Godbolt et al., 2004
R278K
Alzheimer's Disease, Spastic Paraparesis AD : Pathogenic, SP : Pathogenic

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

rs63750524
Coding
Exon 8
Point, Missense
AGA to AGC
0 Raman et al., 2007
R278T
Alzheimer's Disease, Spastic Paraparesis AD : Pathogenic

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.

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

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

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

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

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

rs63749937
Coding
Exon 8
Point, Missense
CTT to GTT
0 Dermaut et al., 2001
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

rs63750324
Coding
Exon 8
Point, Missense
CCA to TCA
0 Marrosu et al., 2006
A285V
Alzheimer's Disease AD : Pathogenic

rs63751139
Coding
Exon 8
Point, Missense
GCT to GTT
0 Rogaev et al., 1995;
Ikeda et al., 1996
L286P
Alzheimer's Disease, Cerebral Amyloid Angiopathy AD : Pathogenic, CAA : Pathogenic

Coding
Exon 8
Point, Missense
CTC to CCC
0 Sánchez-Valle et al., 2007
L286V
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD. Increased Aβ42/Aβ total ratio.

rs63751235
Coding
Exon 8
Point, Missense
CTC to GTC
8 Sherrington et al., 1995
T291P
Alzheimer's Disease, Spastic Paraparesis AD : Pathogenic Unknown; MRI showed marked diffuse atrophy and a signal in the right temporal lobe, compatible with previous bleeding. Point mutation in exon 8 that affects exon 9 splicing, leading to a minor transcript in which exon 9 is excluded. In vitro, this mutation increases both Aβ40 and Aβ42, with a greater effect on Aβ42 and an overall increase in the Aβ42/Aβ40 ratio.

rs63750298
Coding
Exon 8
Point, Missense
ACA to CCA
0 Dumanchin et al., 2006
E318G
None AD : Risk Modifier Unknown. Unknown.

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

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

Coding
Exon 10
Point, Missense
CGC to TGC
0 Jiang et al., 2015
R352_S353insR
Frontotemporal Dementia FTD : Unclear Pathogenicity In-frame insertion of 3 nucleotides in exon 10 resulting in insertion of one amino acid (R) between amino acids R352 and S353.

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

rs63751164
Coding
Exon 10
Point, Missense
ACA to ATA
0 Rogaeva et al., 2001;
Lee et al., 2006
R358Q
Alzheimer's Disease AD : Pathogenic

rs63751174
Coding
Exon 10
Point, Missense
CGA to CAA
0 Rogaeva et al., 2001
S365A
Alzheimer's Disease AD : Pathogenic

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

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

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

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

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

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

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

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

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

Coding
Exon 11
Point, Missense
TTC to ATC
0 Shea et al., 2017
F386S
Alzheimer's Disease AD : Pathogenic

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

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

rs63751066
Coding
Exon 11
Point, Missense
GTT to TTT
0 Raux et al., 2005
L392P
Alzheimer's Disease AD : Pathogenic

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

rs63751416
Coding
Exon 11
Point, Missense
CTG to GTG
0 Campion et al., 1995;
Campion et al., 1995;
Rogaev et al., 1995;
Campion et al., 1999
G394V
Alzheimer's Disease AD : Pathogenic

rs63750929
Coding
Exon 11
Point, Missense
GGT to GTT
0 Rogaeva et al., 2001
A396T
Alzheimer's Disease AD : Pathogenic Unknown; MRI of the proband showed atrophy of the frontal lobes. Unknown; predicted probably damaging in silico.

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

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

Coding
Exon 11
Point, Missense
ATA to ACA
0 Tedde et al., 2016
A409T
Alzheimer's Disease AD : Pathogenic

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; increased Aβ42; Partial loss of γ-secretase mediated cleavage of Notch and β-neurexin.

rs661
Coding
Exon 11
Point, Missense
TGT to TAT
0 Sherrington et al., 1995;
Campion et al., 1995
V412I
Frontotemporal Dementia FTD : Pathogenic

Coding
Exon 11
Point, Missense
GTA to ATA
0 Bernardi et al., 2009
L418F
Alzheimer's Disease AD : Pathogenic

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

rs63750802
Coding
Exon 12
Point, Missense
CTT to CGT
0 Shrimpton et al., 2007
L424F
Alzheimer's Disease AD : Pathogenic

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

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

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

Coding
Exon 12
Point, Missense
CTC to GTC
0 Robles et al., 2009
A426P
Alzheimer's Disease AD : Pathogenic

rs63751223
Coding
Exon 12
Point, Missense
GCC to CCC
0 Poorkaj et al., 1998
A431E
(Jalisco)
Alzheimer's Disease AD : Pathogenic Neuropathology consistent with AD. Predicted to be possibly damaging in silico.

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

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

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

Coding
Exon 12
Point, Missense
GCT to ACT
0 Jiao et al., 2014
L435F
Alzheimer's Disease AD : Pathogenic Widespread cotton-wool plaques in the neocortex, hippocampus, and deep cerebral nuclei contain substantially more Aβ43 than typical plaques. Abundant neurofibrillary tangles in the entorhinal cortex and hippocampus. Mild cerebral amyloid angiopathy. Neuronal loss, depigmentation, and gliosis in the substantia nigra. Increased Aβ42/Aβ40 ratio; decreased Aβ42; decreased Aβ40; Altered γ-secretase activity as demonstrated by reduced cleavage of APP and Notch; Evidence for elevated Aβ43 levels, but conflicting reports; Impaired endoproteolysis of holo-presenilin-1 protein.

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

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

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

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

rs63750470
Coding
Exon 12
Deletion
ACC to ---
0 Ishikawa et al., 2005
869-22_869-23ins18
(ΔE9, Δ9, deltaE9)
Alzheimer's Disease, Spastic Paraparesis AD : Pathogenic Cotton-wool plaques in addition to widespread neurofibrillary tangles and neuritic plaques more typical of AD. Marked cerebral amyloid angiopathy. Insertion of 18 nucleotides (TGGAATTTTGTGCTGTTG) in intron 8, between nucleotide 23 and 22 upstream of exon 9, resulting in exon 9 skipping.

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

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

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

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

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

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

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

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