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PSEN1 (322)
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.
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 (delACG) |
Alzheimer's Disease | AD : Unclear Pathogenicity | Unknown. | Decreased Aβ42 production and undetectable Aβ40 production in vitro. Does not cause a frame-shift. | rs759538127 |
Coding Exon 4 |
Deletion ACG to --- |
0 | Nicolas et al., 2015 |
D40del (delGAC) |
Alzheimer's Disease, Frontotemporal Dementia | AD : Pathogenic | 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. | Decreased Aβ42 and Aβ43 in CSF in one carrier. In cells, increased Aβ42 secretion with no change in Aβ40. In vitro, abrogated Aβ40 production and decreased Aβ42 production. | rs759538127 |
Coding Exon 4 |
Deletion GAC to --- |
0 | Nygaard et al., 2014 |
R41S |
Parkinson's Disease | PD : Unclear Pathogenicity | Unknown, but in one patient, MRI showed moderate frontal cortex atrophy, PiB-PET no amyloid deposition, FDG-PET mild hypometabolism in the lateral temporal lobe. CSF Aβ and tau were normal; phospho-tau elevated. | Unknown. | Coding Exon 4 |
Point, Missense AGA to AGT |
0 | Gatto et al., 2020 | |
R42L |
Alzheimer's Disease | AD : Unclear Pathogenicity | Unknown. | Unknown. | 3677775281 |
Coding Exon 4 |
Point, Missense CGG to CTG |
0 | Koriath et al., 2018 |
P49L |
Alzheimer's Disease | AD : Unclear Pathogenicity | Neuropathology consistent with AD in a carrier who also had the PSEN1 G183V mutation. | Unknown | Coding Exon 4 |
Point, Missense CCA to CTA |
0 | Perrone et al., 2020 | |
E69D |
Alzheimer's Disease | AD : Unclear Pathogenicity | Unknown. | Increased Aβ42 and Aβ40 in cell assay; Aβ42/Aβ40 ratio unchanged. | 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 : Unclear Pathogenicity | Unknown; MRI showed bilateral atrophy, especially in the parietal and temporal lobes in one case, and frontal and temporal atrophy in another. | 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 |
Spastic Paraparesis, Alzheimer's Disease | 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 deleterious by PolyPhen and 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>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 |
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 | |
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, but MRI showed atrophy of the parietal and frontal lobes. | Decreased Aβ42, and particularly Aβ40, in vitro. Increased Aβ42/Aβ40 ratio in assay using isolated proteins and in cultured cells. Predicted probably damaging using in silico algorithms (SIFT, Polyphen2). | Coding Exon 4 |
Point, Missense ACC to GCC |
0 | Ikeda et al., 2013 | |
V103G |
Alzheimer's Disease | AD : Unclear Pathogenicity | Unknown | Unknown, but predicted structural effect and predicted damaging by in silico algorithms (PolyPhen, SIFT, MutationTaster, CADD). | Coding Exon 4 |
Point, Missense GTC to GGC |
0 | Gao et al., 2019 | |
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. | In cell assay, increased Aβ42 and Aβ40; in vitro, decreased Aβ42 production and undetectable Aβ40 production. | 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., 2020 | |
G111W |
Alzheimer's Disease | AD : Pathogenic | Unknown | Unknown | Coding Exon 4 |
Point, Missense GGG to TGG |
0 | Lanoiselée et al., 2017 | |
L113_I114insT (Intron4, p.113+1delG, splice5, InsTAC) |
Myoclonus, Myoclonic seizure, 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 |
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 | |
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 | |
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 3 cases, PiB-PET revealed amyloid in frontal, parietal, and temporal regions, and PET-FDG showed hypometabolism in 3 patients including parietal lobe, precuneus, anterior cingulate, dorsal frontal lobe, and temporal lobe. MRI showed atrophy in frontal, parietal, and temporal cortices. CSF Aβ42 was reduced in one case and CSF phospho-tau elevated in another. | Unknown, but most in silico analyses predict it to be damaging, as do structural data. 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 |
Spastic Paraparesis, Parkinsonism, 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) |
Alzheimer's Disease | AD : Pathogenic | Unknown | Increased Aβ42 and decreased Aβ40 secreted from cells, resulting in increased Aβ42/Aβ40 ratio. However, earlier cell-based results suggested no effect on Aβ40 and Aβ42 levels. | Coding Exon 5 |
Insertion/Deletion CAGAGA to GGA |
0 | Hsu et al., 2018 | |
H131R |
Alzheimer's Disease | AD : Unclear Pathogenicity | Unknown, but PiB-PET showed extensive cortical and striatal amyloid deposition in one patient. Also, FDG-PET showed hypometabolism in precuneus and bilateral temporo-parietal region and reduced blood flow in parietal and temporal lobes. In two patients, MRI showed parietal and temporal atrophy. | Increased Aβ42/Aβ40 ratio in vitro. Also, abrogated pH-sensitivity of Aβ peptide generation in vitro. In silico algorithms predicted benign (Polyphen) and damaging (SIFT). | 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 |
1 | 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>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 |
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>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 |
M146L (A>C) |
Alzheimer's Disease, Pick's disease | AD : Pathogenic | Neuropathology consistent with AD in multiple affected mutation carriers. Pick bodies and Lewy body pathology, as assessed by α-synuclein staining, have been noted in some cases. | Increased Aβ42/Aβ total ratio; increased Aβ42/Aβ40 ratio; increased Aβ42. No change in Aβ38 or Aβ40 levels. Increased tau hyperphosphorylation. 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. In one case, Lewy body pathology in the amygdala, cingulate gyrus, and substantia nigra. | 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, but one patient had posterior cortical atrophy and mild medial temporal atrophy as assessed by MRI. | 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 |
Y159C |
Parkinsonism, Alzheimer's Disease | AD : Pathogenic | Unknown, but in one case, MRI revealed diffuse parietal and hippocampal atrophy, and FDG-PET showed severe hypometabolism in bilateral frontoparieto-temporal cortex. | Unknown, but in silico algorithms predicted probably damaging (Polyphen2) and not tolerated (SIFT). Cryo-EM suggests structural role in PSEN1-APP interaction. CADD score = 28.3. | rs778630379 |
Coding Exon 5 |
TAT to TGT |
0 | Kim et al., 2020 |
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>C) |
Alzheimer's Disease | AD : Pathogenic | Unknown | rs63751484 |
Coding Exon 6 |
Point, Missense TGG to TGC |
0 | Campion et al., 1999 | |
W165C (G>T) (W161C) |
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 | |
W165G |
Alzheimer's Disease | AD : Pathogenic | Unknown; but SPECT showed slight decrease in blood flow to parieto-occipital regions and thalamus in one case. Also, EEG alterations, but normal MRI. | In vitro, increased Aβ42 and Aβ42/Aβ40 ratio; reduced Aβ40. | rs63751010 |
Coding Exon 6 |
Point, Missense TGG to GGG |
0 | Higuchi et al., 2000 |
L166H |
Alzheimer's Disease | AD : Pathogenic | Unknown; MRI showed marked hippocampal atrophy and cortical atrophy, especially in the insula and the peri-insular temporal lobe. SPECT imaging showed bilateral hypometabolism in the parietal and frontal lobes. | Unknown. | rs63750265 |
Coding Exon 6 |
Point, Missense CTT to CAT |
0 | Pantieri et al., 2005 |
L166P |
Alzheimer's Disease, Spastic Paraparesis | AD : Pathogenic | In one individual, numerous Aβ-positive neuritic and cotton-wool plaques throughout the cerebral cortex; abundant Aβ-positive amyloid cores in the cerebellar cortex. In another, robust amyloid pathology in the striatum and cerebellum, and asymmetric tau pathology in the primary sensorimotor cortex contralateral to the side most affected by spasticity. | Increased Aβ42 and Aβ43, decreased total Aβ production. Normal endoproteolysis. Reduced Notch and N-cadherin cleavage. Disrupts endosomes via accumulation of APP β-CTF. Also, dominant-negative effect on wild-type PSEN1, and inhibition of calcium leak 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 TC---T |
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 |
S170_ L171insY (Leu171Tyr) |
Alzheimer's Disease | AD : Pathogenic | Unknown | Unknown | Coding Exon 6 |
Insertion/Deletion --- to TAT |
0 | Koriath et al., 2018 | |
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. Effects on calcium homeostasis, phospho-tau expression, autophagy, expression of mitochondrial fission and fusion proteins, cell viability, and trophic factor function have also been reported. | 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>C) |
Alzheimer's Disease | AD : Pathogenic | Unknown; MRI from two affected mutation carriers showed atrophy of the medial temporal lobe. SPECT showed hypoperfusion of the posterior cingulate gyri and other cortical areas. | N2a cells transfected with mutant PSEN1 secreted significantly more Aβ42 than cells expressing wild-type PSEN1. The Aβ42:Aβ40 ratio was also increased. | Coding Exon 6 |
Point, Missense TTG to TTC |
0 | Kasuga et al., 2009 | |
L173F (G>T) |
Alzheimer's Disease | AD : Pathogenic | Unknown. | Unknown. | Coding Exon 6 |
Point, Missense TTG to TTT |
0 | Jin et al., 2012 | |
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 |
F177V |
Alzheimer's Disease | AD : Pathogenic | Unknown, but MRI showed global brain atrophy, especially in the temporal region and hippocampus in one patient. | Increased Aβ42 and Aβ42/Aβ40 in transfected cells. | Coding Exon 6 |
Point, Missense TTT to GTT |
0 | Gao et al., 2019 | |
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 : Unclear Pathogenicity | Mixed findings. In one case, 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. But in double mutation carrier (G138V and P49L), neuropathology consistent with AD. | 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 mostly degraded by nonsense-mediated decay, but coding for truncated proteins that may cause 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, but MRI of one patient revelaed global cortical atrophy. | Increased Aβ42/Aβ40 ratio, with decreased Aβ42 and Aβ40 production in vitro. In silico algorithms predicted the mutation is damaging and causes structural alterations. Also, mutation is near splice site. | Coding Exon 7 |
Point, Missense GAA to GGA |
0 | Wallon et al., 2012 | |
V191A |
None | AD : Unclear Pathogenicity | Unknown | Decreased Aβ42 secretion in isolated cells, but decrease in Aβ42/Aβ40 did not reach statistical significance. | 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. Also, caused incomplete endoproteolytic processing of PSEN1. | 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. Also inhibits neuroprotection by trophic factors and impairs angiogenesis in KI mice. | 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, but brain imaging showed atrophy and reduced blood flow in temporal, parietal, and frontal lobes. Also, widespread microbleeds were found in brain, brainstem, and cerebellum. Levels of phospho-tau in CSF were elevated, while those of Aβ42 were reduced. | 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>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, 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 | |
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 |
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 |
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 | In one case: neurofibrillary tangles and amyloid plaques throughout the neocortex; occasional plaques in the spinal cord; Lewy bodies in the substantia nigra and cortex; moderate to severe amyloid angiopathy in leptomeningeal, cerebral, and cerebellar vessels. Widespread amyloid deposition in another patient as assessed by PET. | 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 |
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 --- to TAA |
0 | Roeber et al., 2015 | |
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 cells, increased Aβ42 and Aβ43. In vitro, decreased production of Aβ42 and Aβ40, increased Aβ42/Aβ40 ratio. | rs63751320 |
Coding Exon 7 |
Point, Missense TAT to TCT |
0 | Miklossy et al., 2003 |
A260G |
Alzheimer's Disease | AD : Pathogenic, CAA : | Unknown, but CSF bimoarkers were consistent with AD in two patients and MRI revealed mild cortical and hippocampal atrophy in one patient and signs of CAA in two patients. | Unknown | Coding Exon 8 |
Point, Missense GCT to GGT |
0 | Ryman et al., 2014; Piaceri et al., 2020 |
|
A260V |
Alzheimer's Disease | AD : Pathogenic | Neuropathology consistent with AD. Also, perivascular amyloid deposits and Pick-like intra-nueronal inclusions in the dentate gyrus. | Reduced production of Aβ40 and Aβ42; increased Aβ42/Aβ40 ratio in cells and in vitro. | rs63751420 |
Coding Exon 8 |
Point, Missense GCT to GTT |
0 | Rogaev et al., 1995; Ikeda et al., 1996 |
V261F |
Alzheimer's Disease, Spastic Paraparesis | AD : Pathogenic, SP : Pathogenic, CAA : Pathogenic | Neuropathology consistent with AD, with cotton-wool plaques, CAA, and degeneration of spinal lateral pyramidal tracts. | Increased Aβ43 production (prevailing Aβ species) in cells. Decreased Aβ42 and Aβ40 production, and increased Aβ42/Aβ40 ratio in vitro. Also, abolished autoproteolysis. | 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. AD-like CSF levels of Aβ40, Aβ42, Aβ43, tau, and phospho-tau in one carrier, but not in another. | Variable effect on CSF Aβ levels. | 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. | Decreased Aβ40, Aβ42, Aβ43, sAPPα, sAPPβ levels, and Aβ42/Aβ40 ratio in CSF of one carrier. | 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., 2020 | |
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 in 2 carriers; atrophy was minimal or absent in 3 carriers, and cortical amyloid deposition seen in one carrier. | 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. | In cortex, increased Aβ42 and decreased Aβ38 and Aβ43 compared with sporadic AD. In cells, increased Aβ42/Aβ40 ratio; increased Aβ42 compared with wildtype PSEN1, and isolated proteins produce less Aβ40 and Aβ42. In cells, stress vulnerability with increased tau phosphorylation, and impairment of sodium channels, calcium homeostasis, mitochondrial function, AChE activity, and autophagy. | 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 in cells and in vitro. Aβ42 secretion was increased in cells, but production of both Aβ42 and Aβ40 was reduced in vitro, as was endoproteolytic processing of PSEN1. | 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 | |
L282P |
Alzheimer's Disease | AD : Pathogenic | Unknown, but in one patient, MRI revealed mild, diffuse cortical atrophy, and FDG-PET showed severe, bilateral hypometabolism in parietal and temporal cortices. | Unknown, but in silico algorithms predicted probably damaging (Polyphen2) and not tolerated (SIFT). CADD score = 28.5 | Coding Exon 8 |
Point, Missense CTT to CCT |
0 | Kim et al., 2020 | |
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 |
A285S |
Alzheimer's Disease | AD : Pathogenic | Unknown, but in one case, PiB-PET was positive, MRI revealed bilateral hippocampal atrophy, and FDG-PET showed bilateral hypometabolism in the temporal cortex. | Unknown, but in silico algorithms predicted probably damaging (Polyphen2) and tolerable (SIFT). CADD score = 25.9. | Coding Exon 8 |
Point, Missense GCT to TCT |
0 | Kim et al., 2020 | |
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 9 |
Point, Missense ACA to CCA |
0 | Dumanchin et al., 2006 |
W294Ter |
Acute Encephalopathy, Retinitis Pigmentosa | Retinitis Pigmentosa : Pathogenic | Unknown, but MRI of two carriers showed white matter and subcortical lesions, and a third carrier had lesions in the occipital and parietal cortices. All 3 carriers had abnormal EEG recordings. | Unknown, but 3D in silico modeling predicted pronounced structural effects. | Coding Exon 9 |
Point, Nonsense TGG to TAG |
0 | You et al., 2020 | |
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 : Unclear Pathogenicity | Mixed results. Some carriers have AD neuropatholgy, but some do not. | 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 |
P355S |
Alzheimer's Disease, Frontotemporal Dementia | AD : Unclear Pathogenicity | Unkonwn, but MRI revealed microbleeds in cortex, basal ganglia, and subcortical white matter suggestive of amyloid angiopathy. FDG-PET showed bilateral frontotemporal hypometabolism. Lewy body pathology suspected. | Unknown, but cryo-EM data suggest perturbation of γ-secretase catalytic activity. | rs376433615 |
Coding Exon 10 |
Point, Missense CCT to TCT |
0 | Monacelli et al., 2019 |
R358Q |
Alzheimer's Disease | AD : Unclear Pathogenicity | Unknown | Decreased Aβ40 and Aβ42 production and increased Aβ42/Aβ40 ratio in vitro. in cells, increased Aβ40 and Aβ42 secretion, with no significant change in the Aβ42/Aβ40 ratio. | 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 |
G371C |
Alzheimer's Disease | AD : Unclear Pathogenicity | Unknown | Unknown | Coding Exon 10 |
Point, Missense GGT to TGT |
0 | Perrone et al., 2020 | |
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; in one case, imaging showed amyloid deposition in the precuneus and frontal and parietal areas, with mild parietal atrophy and hypometabolism in precuneus, posterior cingulum, inferior parietal lobes, temporal, and frontal lobes. Frontotemporal atrophy and hypometabolism seen in another case. | 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 |
G378R |
AD : Pathogenic | Unknown, but MRI of one patient showed fronto-temporo-parietal atrophy and CSF biomarkers consistent with AD. | Unknown, but predicted deleterious in silico and two other pathogenic mutations in same residue. | Coding Exon 11 |
Point, Missense GGA to CGA |
0 | Ramos-Campoy et al., 2020 | ||
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. | The insertion of one nucleotide in exon 11 is predicted to cause a frameshift. In cells, Aβ40 and Aβ42 production decreased and Aβ42/Aβ40 ratio increased. | 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. Abolishes PSEN1's activity as an 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 | |
Y389H |
Parkinsonism, Alzheimer's Disease | AD : Pathogenic | Unknown, but in two cases, amyloid-PET was positive. MRI revealed mild, diffuse cortical atrophy in one case, and severe frontotemporal atrophy in another. FDG-PET showed bilateral hypometabolism in parietal and temporal cortices in one case. | Unknown, but in silico algorithms predicted probably damaging (Polyphen2) and not tolerable/damaging (SIFT). CADD score = 26.9. | Coding Exon 11 |
Point, Missense TAC to CAC |
0 | Park et al., 2020; Kim et al., 2020 |
|
Y389S |
Alzheimer's Disease | AD : Pathogenic | Unknown, but one case had Aβ accumulation (PiB-PET+), with mild, diffuse cortical atrophy (MRI), and bilateral hypometabolism in the parieto-temporal cortex (FDG-PET). | Unknown, but predicted probably damaging by in silico algorithms Polyphen2 and SIFT. CADD score = 26.8. | Coding Exon 11 |
Point, Missense TAC to TCC |
0 | Kim et al., 2020 | |
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 Aβ40 and Aβ42 production with Aβ42/Aβ40 ratio unchanged in cells; reduced Aβ40 production and increased Aβ42/Aβ40 ratio in vitro. | 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 : Unclear Pathogenicity | 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 in one patient. In another, fronto-temporal atrophy was predominant, as revelaed by CT and MRI. | 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 several patients with motor impairments. In one case, Lewy body pathology. | 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, inluding iPSC-derived neurons, knockin rats, 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 |
1 | 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. | Decreased Aβ40 and Aβ42 production, and increased Aβ42/Aβ40 ratio in vitro. | 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. | In vitro, moderately increased Aβ40 and Aβ42 production; Aβ42/Aβ40 ratio unchanged. In cells, increased Aβ42 secretion; Aβ42/Aβ40 unchanged. | 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 |
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, c.869-2A>G) |
Alzheimer's Disease | AD : Pathogenic | Unknown; in one patient, MRI showed supratentorial atrophy, particularly of parietal and occipital cortex. Also, reduced Aβ42 in CSF. | 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, c.869-1G>A) |
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 |
|
c.869-22_869-23ins18 (ΔE9, Δ9, deltaE9) |
Spastic Paraparesis, Alzheimer's Disease | 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 | |
c.*947G>A |
AD : Unclear Pathogenicity | Unknown, associated with increased thickness in the inferior frontal and orbitofrontal cortices, and basal ganglia | Unknown | rs7523 |
Non-Coding 3' UTR |
Point |
0 | Seo et al., 2020 |