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Search Results
PSEN2 (90)
The gene PSEN2 encodes presenilin-2, a subunit of γ-secretase, the aspartyl protease responsible for Aβ generation. Missense mutations in PSEN2 are a rare cause of early onset Alzheimer's disease.
Mutation | Clinical Phenotype |
Pathogenicity | Neuropathology | Biological Effect | Genomic Position | Genomic Region | Mutation Type Codon Change |
Research Models |
Primary Papers |
---|---|---|---|---|---|---|---|---|---|
T18M |
Alzheimer's Disease, MSA-P | AD : Benign, PD : Not Classified | Unknown. |
Unknown; predicted pathogenic in silico (CADD>20). |
rs143061887 |
Exon 4 | Point, Missense ACG to ATG |
0 | Blauwendraat et al., 2016 |
A23A |
Alzheimer's Disease | AD : Benign | Unknown. |
Unknown, but in silico algorithm predicted non-deleterious (CADD = 5.75). |
rs11405 |
Exon 4 | Point, Silent GCT to GCC |
0 | Eryilmaz et al., 2021 |
R29H |
Alzheimer's Disease | AD : Uncertain Significance | Not applicable. |
Unknown. |
Exon 4 | Point CGC to CAC |
0 | Guerreiro et al., 2010 | |
G34S |
Alzheimer's Disease | AD : Benign | Unknown, but in one case, brain MRI showed multiple ischemic foci of the bilateral frontal-parietal lobe and brain atrophy. |
Unchanged Aβ42/Aβ40 ratio. |
Exon 4 | Point GGC to AGC |
0 | Sleegers et al., 2004 | |
N43N |
Alzheimer's Disease | AD : Benign | Unknown. |
Unknown. |
rs6759 |
Exon 4 | Point, Silent AAC to AAT |
0 | Eryilmaz et al., 2021 |
R62C |
Alzheimer's Disease, None | AD : Benign | Unknown. |
Reduced levels of CSF Aβ43 and Aβ42, and increased Aβ40; decreased Aβ42/Aβ40 ratio in one carrier. |
rs150400387 |
Exon 5 | Point CGC to TGC |
0 | Sleegers et al., 2004 |
R62H |
Alzheimer's Disease, Frontotemporal Dementia, Parkinson's Disease Dementia | AD : Benign, FTD : Not Classified | Unknown. In two carriers, CSF biomarker levels were variable. |
In two carriers, CSF Aβ peptide levels were variable. In cells, unchanged Aβ42/Aβ40 ratio; unchanged Aβ42; No change in proteolytic products PSEN2-CTF and PSEN2-NTF. |
rs58973334 |
Exon 5 | Point, Missense CGC to CAC |
0 | Cruts et al., 1998; Gallo et al., 2010 |
C65Y |
svPPA | svPPA : Not Classified | Unknown. In one case, CSF biomarkers (Aβ42, tau, and phospho-tau) were inconsistent with AD. |
Unknown. In silico predictions were mixed (PHRED-scaled CADD = 19.4). |
rs766446160 |
Exon 5 | Point, Missense TGT to TAT |
0 | Ramos-Campoy et al., 2020 |
P69A |
Alzheimer's Disease | AD : Benign | Unknown. |
Unknown, but scored low for deleteriousness in silico (PHRED-scaled CADD <20). |
Exon 5 | Point, Missense CCC to GCC |
0 | Dobricic et al., 2012 | |
R71W |
Alzheimer's Disease, None, Parkinson's Disease Dementia | AD : Benign | Leukoencephalopathy with periventricular white-matter lacunar infarctions. |
Unchanged Aβ42/Aβ40 ratio; Reduces the stability of the presenilin-2 protein and impairs Notch signaling. |
rs140501902 |
Exon 5 | Point, Missense CGG to TGG |
0 | Sleegers et al., 2004 |
L79P |
Alzheimer's Disease | AD : Not Classified | Unknown, but CSF biomarkers consistent with AD. |
Unknown, but some in silico algorithms predicted damaging (PHRED-scaled CADD>20). |
rs760961297 |
Exon 5 | Point, Missense CTG to CCG |
0 | Ramos-Campoy et al., 2020 |
K82R |
Alzheimer's Disease | AD : Not Classified | Unknown; neuroimaging showed diffuse cortical atrophy, especially in the posterior region and mild hippocampal atrophy. FDG-PET showed widespread hypometabolism. PIB-PET showed amyloid deposition in the frontal lobe, lateral temporal lobe, parietal lobe, posterior cingulate cortex, precuneus, and striatum. |
Aβ42/Aβ40 ratio, and Aβ42 and Aβ40 secretion similar to control in cellular assay. |
Exon 5 | Point, Missense AAA to AGA |
0 | Shi et al., 2015 | |
K82fs |
Frontotemporal Dementia | Tauopathy consistent with Pick's Disease : Not Classified | Neuropathology consistent with Pick's disease. |
Frameshift starting at K82; reduced mutant protein in frontal cortex and hippocampus. |
Exon 5 | Deletion AAA to A-- |
0 | Perrone et al., 2018 | |
A85V |
Alzheimer's Disease, Dementia with Lewy Bodies | AD : Benign, DLB : Not Classified | In one carrier: amyloid deposition; neurofibrillary changes; diffuse Lewy bodies in the neocortex. |
No detectable effect on Aβ40 and Aβ42 secretion, nor the Aβ42/Aβ40 ratio in transfected cells. |
rs63750048 |
Exon 5 | Point, Missense GCG to GTG |
0 | Piscopo et al., 2008 |
I100I |
Late-onset | AD : Likely Benign | Unknown. |
Unknown, but predicted benign in silico (PHRED-scaled CADD score = 6.52). |
rs200801915 |
Exon 5 | ATC to ATT |
0 | Wang et al., 2023 |
V101M |
Alzheimer's Disease | AD : Not Classified | Unknown. |
Unknown; predicted probably damaging in silico. |
Exon 5 | Point, Missense GTG to ATG |
0 | Sala Frigerio et al., 2015 | |
K115Efs* (K115Efx10) |
Alzheimer's Disease | AD : Uncertain Significance | Neuropathology was consistent with AD. |
The deletion of two nucleotides from exon 5 leads to a frameshift and ultimately to a premature stop codon in exon 6. In patient fibroblasts, secretion of Aβ40 was decreased, and Aβ38 and Aβ42 were undetectable. Wild-type PSEN2 levels were also decreased. Alternatively spliced transcripts of the mutant allele were detected in brain. |
Exon 5 | Deletion AAG to A-- |
0 | Jayadev et al., 2010 | |
G117Ter (G117X) |
Alzheimer's Disease | AD : Not Classified | Unknown |
Unknown, but in silico prediction of deleteriousness was high (CADD = 40). |
Exon 5 | Point, Nonsense GGA to TGA |
0 | Mao et al., 2021 | |
T122P |
Alzheimer's Disease | AD : Likely Pathogenic | Unknown. |
Increased Aβ42/Aβ40 ratio; increased Aβ42; No change in proteolytic products PSEN2-CTF and PSEN2-NTF. |
rs63749851 |
Exon 6 | Point, Missense ACG to CCG |
0 | Finckh et al., 2000 |
T122R |
Atypical Dementia | Atypical Dementia : Not Classified | Variable cortical and subcortical atrophy. |
Reduced calcium ion released from intracellular stores. |
rs28936380 |
Exon 6 | Point, Missense ACG to AGG |
0 | Binetti et al., 2003 |
P123L |
Alzheimer's Disease | AD : Not Classified | Unknown; Neuroimaging showed diffuse cortical atrophy, predominantly in the right hemisphere. FDG-PET showed hypoperfusion in the right temporal and parietal regions. |
Increased Aβ42 and decreased Aβ40 secretion in cells, resulting in an approximately 2-fold increase in the Aβ42/Aβ40 ratio. |
Exon 6 | Point, Missense CCA to CTA |
0 | Xia et al., 2015 | |
E126K |
Alzheimer's Disease | AD : Not Classified | Unknown. |
Unknown; predicted probably damaging in silico (PHRED-scaled CADD >20). |
Exon 6 | Point, Missense GAG to AAG |
0 | Müller et al., 2014 | |
E126fs |
Alzheimer's Disease | AD : Not Classified | Unknown; neuroimaging showed hippocampal and parahippocampal atrophy. |
Reduced Aβ42 and Aβ40 secretion, as well as the Aβ42/Aβ40 ratio in a cellular assay. |
Exon 6 | Insertion GAG.GAC to GAA.GGA |
0 | El Kadmiri et al., 2014 | |
S130L |
Alzheimer's Disease, None, Parkinson's Disease Dementia | AD : Uncertain Significance | Neuropathology consistent with AD at autopsy in at least one case. Reduced CSF Aβ43/Aβ40 and Aβ42/Aβ40 ratios in another case, with slightly elevated tau and normal phospho-tau CSF levels. |
In transfected cells, unchanged Aβ42/Aβ40 ratio, Aβ42, PSEN2-CTF, and PSEN2-NTF. Altered calcium signaling in cells.
|
rs63750197 |
Exon 6 | Point, Missense TCG to TTG |
0 | Sorbi et al., 2002; Tedde et al., 2003 |
L135R |
Frontotemporal Dementia | FTD : Not Classified | Unknown |
Unknown, but PHRED-scaled CADD score was above 20 suggesting a damaging effect. |
rs1272015481 |
Exon 6 | Point, Missense CTC to CGC |
0 | Koriath et al., 2018 |
V139M |
Alzheimer's Disease, None | AD : Benign | Bilateral hypoperfusion in the parietal-temporal lobes. |
In transfected cells, Aβ42 and Aβ40 levels, as well as Aβ42/Aβ40 ratio, were not significantly different from control. |
Exon 6 | Point, Missense GTG to ATG |
0 | Bernardi et al., 2008 | |
N141Y |
Alzheimer's Disease | AD : Likely Pathogenic | Proband had autopsy-confirmed AD with severe brain atrophy and numerous plaques and neurofibrillary tangles. |
Unknown; predicted damaging in silico. |
rs61761208 |
Exon 6 | Point, Missense AAC to TAC |
0 | Niu et al., 2014 |
N141D |
Alzheimer's Disease | AD : Not Classified | Unknown |
Unknown, but 3 algorithms predict damaging with a PHRED CADD score of 24.9. |
Exon 6 | Point, Missense AAC to GAC |
0 | Wang et al., 2019 | |
N141I |
Alzheimer's Disease | AD : Pathogenic | Extensive amyloid plaques; Extensive neurofibrillary tangles (typically a Braak score of V or VI); α-synuclein inclusions, especially in the amygdala; Rare TDP-43 pathology; Hippocampal sclerosis. |
Increased Aβ42/Aβ40 ratio; increased Aβ42; No change in PSEN2-CTF and PSEN2-NTF. Altered microglial phenotype. In 3-D brain organoids, elevated Aβ42/Aβ40 ratio, asynchronous calcium transients, and neuronal hyperactivity. Cytokine overproduction in mice. Exon 6 skipping in ~10% of mutated transcripts, reduced mRNA stability.
|
rs63750215 |
Exon 6 | Point, Missense AAC to ATC |
5 | Levy-Lahad et al., 1995; Rogaev et al., 1995 |
N141S |
Alzheimer's Disease | AD : Not Classified | Unknown. |
Unknown, but in silico algorithms predicted damaging (CADD > 20). |
Exon 6 | Point, Missense AAC to AGC |
0 | Mao et al., 2021 | |
L143H |
None | AD : Not Classified | Not applicable. |
Unknown, but in silico analysis predicts a deleterious effect (PHRED-scaled CADD > 20). |
Exon 6 | Point, Missense CTC to CAC |
0 | Guerreiro et al., 2010 | |
I146T |
Alzheimer's Disease | AD : Uncertain Significance | Unknown |
Unknown, but predicted damaging in silico (CADD > 20). |
rs1215971988 |
Exon 6 | ATC to ACC |
0 | Mao et al., 2021 |
S147N |
Alzheimer's Disease | AD : Not Classified | Unknown |
Unknown, but in silico analyses predicted damaging (CADD>20). |
Exon 6 | Point, Missense AGC to AAC |
0 | Mao et al., 2021 | |
V148I |
Alzheimer's Disease | AD : Benign | Unknown. |
Unchanged Aβ42/Aβ40 ratio; unchanged Aβ42; No change in proteolytic products PSEN2-CTF and PSEN2-NTF. |
rs63750812 |
Exon 6 | Point, Missense GTC to ATC |
0 | Lao et al., 1998 |
I149T |
Alzheimer's Disease | AD : Not Classified | Unknown |
Unknown, but in silico analysis predicts a damaging effect (PHRED-scaled CADD >20). |
Exon 6 | Point, Missense ATC to ACC |
0 | Perrone et al., 2020 | |
V150M |
Alzheimer's Disease | AD : Not Classified | Unknown |
Unknown, but predicted damaging in silico (PHRED-scaled CADD score >20). |
rs866044092 |
Exon 6 | Point, Missense GTG to ATG |
0 | Gao et al., 2019 |
T153S |
Alzheimer's Disease | AD : Not Classified | Unknown |
Unknown, but in silico analysis suggests damaging effect (PHRED-scaled CADD score =25.9).
|
Exon 6 | Point, Missense ACC to AGC |
0 | Perrone et al., 2020 | |
K161R |
Alzheimer's Disease | AD : Not Classified | Unknown. |
Unknown, but in silico analysis predicted a damaging effect (PHRED-scaled CADD score = 32). |
Exon 6 | Point, Missense AAG to AGG |
0 | Wallon et al., 2012 | |
R163C |
Alzheimer's Disease | AD : Uncertain Significance | Unknown |
Unknown, but predicted damaging by in silico algorithms. |
rs200931244 |
Exon 6 | Point, Missense CGC to TGC |
0 | Gao et al., 2019 |
R163H |
None | AD : Benign | Not applicable. |
Unknown, but in silico analysis predicted a damaging effect (PHRED-scaled CADD score > 20). |
rs778936527 |
Exon 6 | Point, Missense CGC to CAC |
0 | Puschmann et al., 2009 |
H169N |
Alzheimer's Disease, Frontotemporal Dementia, Progressive Nonfluent Aphasia | AD : Uncertain Significance, FTD : Not Classified | Unknown; neuroimaging showed mild atrophy and widespread hypometabolism. PIB-PET showed amyloid deposition in the AD case, but no amyloid deposition in the FTD case. |
Unknown. |
Exon 7 | Point, Missense CAT to AAT |
0 | Shi et al., 2015 | |
M174V |
Alzheimer's Disease, Frontotemporal Dementia | AD : Benign | Unknown; imaging has shown frontal atrophy and hypoperfusion in temporoparietal regions. |
Decreased Aβ40 modestly without significantly changing the Aβ42/Aβ40 ratio in a cell assay. |
rs61757781 |
Exon 7 | Point, Missense ATG to GTG |
0 | Andreoli et al., 2008; Clarimón et al., 2008; Guerreiro et al., 2010 |
M174I |
Alzheimer's Disease | AD : Not Classified | Neuropathology consistent with AD. |
Unknown, but in silico algorithm predicted damaging (PHRED-scaled CADD > 20). |
Exon 7 | Point, Missense ATG to ATA |
0 | Wong et al., 2020 | |
S175F |
Alzheimer's Disease | AD : Not Classified | Unknown, but in one case brain imaging showed atrophy and hypometabolism consistent with AD. |
Unknown, but multiple in silico algorithms suggest it is damaging. |
Exon 7 | Point, Missense TCT to TTT |
0 | Guven et al., 2021 | |
S175C |
Alzheimer's Disease | AD : Not Classified | Unknown; MRI showed focal atrophy in the medial temporal lobe; SPECT showed bilateral hypoperfusion in temporoparietal regions. |
Unknown, but in silico analyses predicted a damaging effect (PHRED-scaled CADD score > 20). |
rs775145486 |
Exon 7 | Point, Missense TCT to TGT |
0 | Piscopo et al., 2010 |
F183S |
Alzheimer's Disease | AD : Not Classified | Unknown. |
Unknown, but in silico analysis predicted a damaging effect (PHRED-scaled CADD score >20). |
Exon 7 | Point, Missense TTC to TCC |
0 | Wojtas et al., 2012 | |
Y195C |
Frontotemporal Dementia | FTD : Not Classified | Unknown |
Unknown, but the PHRED-scaled CADD score was > 20 suggesting a damaging effect. |
rs200410369 |
Exon 8 | Point, Missense TAC to TGC |
0 | Koriath et al., 2018 |
G212V |
Alzheimer's Disease | AD : Not Classified | Neuropathology consistent with AD. |
Unknown; predicted pathogenic in silico (PHRED-scaled CADD score = 27.7). |
Exon 8 | Point, Missense GGG to GTG |
0 | Marín-Muñoz et al., 2016 | |
V214L |
Alzheimer's Disease | AD : Benign | Unknown; neuroimaging showed diffuse cortical atrophy and widespread hypometabolism. |
Unknown; structural changes were predicted in silico, especially at amino acids 214, 219, and 220. PolyPhen2 predicted a probably or possibly damaging effect; PHRED-scaled CADD score = 24.3. |
Exon 8 | Point, Missense GTG to TTG |
0 | Youn et al., 2014 | |
H220Y |
Alzheimer's Disease | AD : Not Classified | Unknown |
Unknown, but in silico algorithms predict damaging (CADD > 20). |
Exon 8 | Point, Missense CAC to TAC |
0 | Mao et al., 2021 | |
L225P |
Alzheimer's Disease | AD : Not Classified | Unknown. |
Unknown, but PHRED-scaled CADD score was above 20, suggesting a damaging effect. |
rs763295042 |
Exon 8 | Point, Missense CTG to CCG |
0 | Koriath et al., 2018 |
Q228L |
Alzheimer's Disease | AD : Not Classified | Unknown. |
Unknown, but in silico analysis predicted a damaging effect (PHRED-scaled CADD score >20). |
rs63750880 |
Exon 8 | Point, Missense CAG to CTG |
0 | Zekanowski et al., 2003 |
Y231C |
Frontotemporal Dementia | FTD : Not Classified | Unknown; MRI showed diffuse subcortical and cortical atrophy, particularly in the frontotemporoparietal lobes. |
Unknown but in silico analysis predicted a damaging effect (PHRED-scaled CADD score = 27.8). |
Exon 8 | Point, Missense TAC to TGC |
0 | Marcon et al., 2009 | |
I235F |
Alzheimer's Disease, None | AD : Not Classified | Unknown. |
Increased Aβ42/Aβ40 ratio in cells. |
Exon 8 | Point, Missense ATC to TTC |
0 | Lee et al., 2014 | |
S236S |
AD : Benign | Unknown, but in one patient PET showed amyloid deposition and MRI revealed atrophy in temporo-insular cortices. FDG-PET showed diffuse hypometabolism in the cortex and striatum. |
Unknown. In silico analyis predicted it is benign (PHRED-scaled CADD = 7.2), but could alter splicing. |
rs61730652 |
Exon 8 | Point, Silent AGT to AGC |
0 | Coppola et al., 2020 | |
A237V |
Alzheimer's Disease | AD : Uncertain Significance | Neuropathology consistent with AD. |
Unknown; predicted possibly damaging in silico. |
rs200670135 |
Exon 8 | Point, Missense GCG to GTG |
0 | Sassi et al., 2014 |
L238F |
Alzheimer's Disease | AD : Uncertain Significance | Unknown. |
Increased Aβ42/Aβ40 ratio in cellular assay. |
Exon 8 | Point, Missense CTC to TTC |
0 | Sala Frigerio et al., 2015 | |
L238P |
Alzheimer's Disease | AD : Uncertain Significance | Unknown; MRI showed supratentorial cortical atrophy, particularly atrophy of the parietal cortex. |
Unknown; predicted damaging in silico (PHRED-scaled CADD score = 26.7). |
Exon 8 | Point, Missense CTC to CCC |
0 | Blauwendraat et al., 2016 | |
M239V |
Alzheimer's Disease | AD : Pathogenic | Diffuse cerebral atrophy; Senile plaques; Neurofibrillary tangles (stage VI of Braak and Braak); Ectopic neurons in the subcortical white matter; Extracellular "ghost" neurofibrillary tangles. |
Increased Aβ42/Aβ40 ratio; increased Aβ42; No change in proteolytic products PSEN2-CTF and PSEN2-NTF. |
rs28936379 |
Exon 8 | Point, Missense ATG to GTG |
0 | Rogaev et al., 1995 |
M239T |
Alzheimer's Disease | AD : Uncertain Significance | Unknown, but florbetapir-PET indicated amyloid accumulation in one carrier and CSF biomarkers were consistent with AD in another. Atrophy of the parietal lobe was observed in both patients, with one of them also having occipital cortex atrophy. In the latter patient, FDG-PET suggested hypometabolism in parietal, temporal, and occipital cortices. |
Unknown, but in silico algorithms predicted deleterious (PHRED-scaled CADD score > 20). |
Exon 8 | Point, Missense ATG to ACG |
0 | Li et al., 2021; Jiao et al., 2021; Mao et al., 2021 |
|
M239I |
Alzheimer's Disease | AD : Pathogenic | Moderate cortical atrophy; Numerous neurofibrillary tangles; Numerous senile plaques, especially in the amygdala. |
Increased Aβ42/Aβ40 ratio; increased Aβ42; No change in proteolytic products PSEN2-CTF and PSEN2-NTF; Reduced calcium release. |
rs63749884 |
Exon 8 | Point, Missense ATG to ATA |
0 | Finckh et al., 2000 |
A252T |
None | AD : Benign | Not applicable. |
Decreased Aβ42 and Aβ40 in cells, without altering Aβ42/Aβ40 ratio. |
rs138836272 |
Exon 8 | Point, Missense GCG to ACG |
0 | Guerreiro et al., 2010 |
A258T |
None | AD : Benign | Not applicable. |
Unknown, but in silico analysis predicted a damaging effect (PHRED-scaled CADD = 26.8). |
rs148238688 |
Exon 8 | Point, Missense GCC to ACC |
0 | Sala Frigerio et al., 2015 |
A258V |
Alzheimer's Disease | AD : Not Classified | Unknown |
Reduced Aβ40 and Aβ42 in a cellular assay without affecting the Aβ42/Aβ40 ratio. |
rs14443227784 |
Exon 8 | Point, Missense GCC to GTC |
0 | Yagi et al., 2014 |
R284G |
AD : Likely Pathogenic | Unknown. |
Increased Aβ42 and Aβ42/Aβ40 in a cell assay. |
rs1208742830 |
Exon 9 | Point, Missense AGA to GGA |
0 | Lanoiselée et al., 2017 | |
P287P |
AD : Likely Benign | Unknown, but associated with increased glucose metabolism in the bilateral fronto-temporo-parietal cortices. |
Unknown, but in silico analysis did not predict a damaging effect (PHRED-scaled CADD = 11.4). |
rs75733498 |
Exon 9 | Point, Silent CCC to CCT |
0 | Jia et al., 2020 | |
c.887-3C>T |
Alzheimer's Disease | AD : Not Classified | Unknown |
Unknown, but in silico analysis does not predict a damaging effect (PHRED-scaled CADD score of 9.977). |
rs1230394996 |
Intron 9 | Point |
0 | Wang et al., 2019 |
M298T |
Alzheimer's Disease | AD : Likely Pathogenic | Unknown. |
Unknown. Some, but not all, in silico algorithms predicted damaging (PHRED-scaled CADD>20). |
rs1482790603 |
Exon 10 | Point, Missense ATG to ACG |
0 | Wang et al., 2019 |
T301M |
Alzheimer's Disease | AD : Benign | Unknown. |
Unchanged Aβ42/Aβ40 ratio. |
rs144277432 |
Exon 10 | Point, Missense ACG to ATG |
0 | Croes et al., 2004 |
K306fs |
Alzheimer's Disease | AD : Not Classified | Unknown; neuroimaging in one case showed cortical atrophy. |
Unknown; the deletion of a single nucleotide (A) in exon 9 is predicted to result in a frameshift at codon 306. |
Exon 10 | Deletion AAG.CTG to AGC.TGG |
0 | El Kadmiri et al., 2014 | |
P334A |
Alzheimer's Disease, None | AD : Benign | Not applicable. |
Moderately decreased Aβ40 without changing Aβ42/Aβ40 ratio. |
Exon 11 | Point, Missense CCT to GCT |
0 | Lee et al., 2014 | |
P334R |
Alzheimer's Disease, None | AD : Benign | Not applicable. |
Unknown, but predicted not damaging in silico (PHRED-scaled CADD score = 16.3). |
rs63750207 |
Exon 11 | Point, Missense CCT to CGT |
0 | Lleó et al., 2002 |
P348L |
Alzheimer's Disease | AD : Not Classified | Unknown. |
Decreased Aβ40; increased Aβ42/Aβ40 ratio in cell assay. |
Exon 11 | Point, Missense CCA to CTA |
0 | Blauwendraat et al., 2016 | |
G359Lfs*74 (Intron 11 delA) |
Alzheimer's Disease, Mild Cognitive Impairment | AD : Not Classified, MCI : Not Classified | Unknown, but MRI of MCI patient revealed mild atrophy in the hippocampus, and SPECT showed decreased metabolism in posterior and temporal cortices. |
Deletion of an adenine in intron 11 resulting in exon 12 skipping and a frameshift starting at codon G359; new termination codon in the 3' UTR. Reduced PSEN2 levels due to instability. CADD-PHRED = 23.9. |
Intron 11 | Point |
0 | Perrone et al., 2018 | |
G359Lfs*74 (Intron 11 delAG) |
Amyotrophic Lateral Sclerosis | ALS : Not Classified | Unknown. |
Deletion of an adenine in intron 11 resulting in exon 12 skipping and a frameshift starting at codon G359; new termination codon in the 3' UTR. |
Intron 11 | Deletion |
0 | Perrone et al., 2018 | |
I368F |
Alzheimer's Disease | AD : Not Classified | Unknown |
Unknown, but multiple in silico algorithms predicted a damaging effect (PHRED-scaled CADD >20). |
Exon 12 | Point, Missense ATC to TTC |
0 | Mao et al., 2021 | |
F369S |
Alzheimer's Disease | AD : Not Classified | Unknown, but MRI in one case showed progressive brain atrophy, particularly in the temporal lobe and hippocampus. |
Unknown, but in silico algorithms predict damaging effect (CADD > 20) |
Exon 12 | Point, Missense TTC to TCC |
0 | Wan et al., 2021 | |
A377V |
Alzheimer's Disease, None | AD : Benign | Not applicable. |
Unknown. |
Exon 12 | Point, Missense GCG to GTG |
0 | Lee et al., 2014 | |
A379D |
Alzheimer's Disease | AD : Not Classified | Unknown |
Unknown, but predicted damaging in silico. PHREDD CADD score = 27.1 |
Exon 12 | Point, Missense GCC to GAC |
0 | Wang et al., 2019 | |
T388M |
bvFTD | bvFTD : Not Classified | Unknown. CSF biomarker levels (Aβ42, tau, phospho-tau) were not consistent with AD. |
Unknown, but multiple in silico algorithms predicted damaging (CADD >20). |
rs143549266 |
Exon 12 | Point, Missense ACG to ATG |
0 | Ramos-Campoy et al., 2020 |
C391R |
Mild Cognitive Impairment | MCI : Not Classified | Unknown. |
Unknown, but PHRED-scaled CADD = 28.6, suggesting a deleterious effect. |
Exon 12 | TGC to CGC |
0 | Mathioudakis et al., 2023 | |
V393M |
Alzheimer's Disease | AD : Benign | Unknown; bilateral hypometabolism in the parieto-occipital regions. |
Unchanged Aβ42/Aβ40 ratio in cells. In one assay, reduced secretion of Aβ4 and Aβ42, in another, Aβ42 secretion was unchanged. |
rs142690225 |
Exon 12 | Point, Missense GTG to ATG |
0 | Lindquist et al., 2008 |
A394Pfs*8 |
Alzheimer's Disease | AD : Not Classified | Unknown |
Unknown |
Exon 12 | Deletion GCC to CCA |
0 | Jiao et al., 2021 | |
A415S |
Alzheimer's Disease | AD : Not Classified | Unknown, but MRI revealed global cerebral and cerebellar atrophy. CSF biomarkers were consistent with AD. |
Unknown, but in silico algorithm predicted damaging (PHRED-scaled CADD > 20). |
Exon 13 | Point, Missense GCC to TCC |
0 | Wong et al., 2020 | |
T421M |
Alzheimer's Disease | AD : Benign | Unknown |
Decreased both Aβ42 and Aβ40, without affecting Aβ42/Aβ40 ratio in cellular assay. |
rs756609078 |
Exon 13 | Point, Missense ACG to ATG |
0 | Yagi et al., 2014 |
T430M |
Alzheimer's Disease | AD : Not Classified | Right frontotemporal hypoperfusion. |
Unknown, but in silico analysis predicted a damaging effect (PHRED-scaled CADD score = 31). |
rs63750666 |
Exon 13 | Point, Missense ACG to ATG |
0 | Ezquerra et al., 2003 |
R435Q |
Alzheimer's Disease | AD : Uncertain Significance | Unknown. |
Unknown, but in silico algorithms predict damaging (PHRED-scaled CADD = 22.1). |
rs201922151 |
Exon 13 | CGG to CAG |
0 | |
P436L |
Alzheimer's Disease | Dementia : Not Classified | Unknown, but MRI of one carrier showed bilateral atrophy of the temporal lobe and hippocampus. |
Unknown. |
Exon 13 | Point, Missense CCG to CTG |
0 | Han et al., 2020 | |
D439A |
Alzheimer's Disease | AD : Likely Benign | Unknown; imaging showed moderate cortical atrophy in the frontal and parietal regions. |
MIxed results in vitro. |
rs63750110 |
Exon 13 | Point, Missense GAC to GCC |
0 | Lleó et al., 2001 |
c.*71C>A |
Alzheimer's Disease | AD : Likely Pathogenic | Unknown, but MRI scan of one case showed widening of the sulcus, fissure, and temporal horn, with decreased hippocampal volume. Also, FDG-PET showed hypometabolism in the bilateral frontal, parietal, and temporal lobes. Five affected carriers had CSF Aβ42, total tau, and phospho-tau consistent with AD. |
Reduction of binding of PSEN2 expression suppressor miR-183-5p, possibly causing increased Aβ42/Aβ40 ratio. |
rs537889666 |
Exon 13, 3'UTR | Point |
0 | Pang et al., 2021; Jia et al., 2020 |