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PSEN2 (80)

Mutation	Clinical Phenotype	Pathogenicity	Neuropathology	Biological Effect	Genomic Position	Genomic Region	Mutation Type Codon Change	Research Models	Primary Papers
T18M	Parkinson's Disease	PD : Unclear Pathogenicity	Unknown.	Unknown; predicted pathogenic in silico.	rs143061887	Coding Exon 4	Point, Missense ACG to ATG	0	Blauwendraat et al., 2016
A23A	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown, but 3 of 4 carriers (also carrying PSEN2 N43N) had atrophy consistent with AD as assessed by MRI.	Unknown	rs11405	Coding Exon 4	Point, Silent GCT to GCC	0	Eryilmaz et al., 2021
R29H	None	AD : Benign	Not applicable.	Unknown.		Coding Exon 4	Point CGC to CAC	0	Guerreiro et al., 2010
G34S	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown.	Unchanged Aβ42/Aβ40 ratio.		Coding Exon 4	Point GGC to AGC	0	Sleegers et al., 2004
N43N	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown, but 3 of 4 carriers (also carrying PSEN2 A23A) had atrophy consistent with AD as assessed by MRI.	Unknown.	rs6759	Coding Exon 4	Point, Silent AAC to AAT	0	Eryilmaz et al., 2021
R62C	Alzheimer's Disease, None	AD : Unclear Pathogenicity	Unknown.	Reduced levels of CSF Aβ43 and Aβ42, and increased Aβ40; decreased Aβ42/Aβ40 ratio in one carrier.	rs150400387	Coding Exon 5	Point CGC to TGC	0	Sleegers et al., 2004; Ertekin-Taner et al., 2008; Brouwers et al., 2008
R62H	Alzheimer's Disease, Frontotemporal Dementia, Parkinson's Disease Dementia	AD : Benign, FTD : Benign	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	Coding Exon 5	Point, Missense CGC to CAC	0	Cruts et al., 1998; Gallo et al., 2010
P69A	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown.	Unknown.		Coding Exon 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	Coding Exon 5	Point, Missense CGG to TGG	0	Sleegers et al., 2004
K82fs	Frontotemporal Dementia	Tauopathy consistent with Pick's Disease : Unclear Pathogenicity	Neuropathology consistent with Pick's disease.	Frameshift starting at K82; reduced mutant protein in frontal cortex and hippocampus.		Coding Exon 5	Deletion AAA to A--	0	Perrone et al., 2018
K82R	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown; neuroimaging showed diffuse cortical atrophy, especially in the posterior region and mild hippocampal atrophy. FDG-PET showed widespread hypometabolism. PIB-PET showed amyloid deposition in the frontal lobe, lateral temporal lobe, parietal lobe, posterior cingulate cortex, precuneus, and striatum.	Unknown.		Coding Exon 5	Point, Missense AAA to AGA	0	Shi et al., 2015
A85V	Alzheimer's Disease, Dementia with Lewy Bodies	AD : Pathogenic, DLB : Unclear Pathogenicity	Amyloid deposition; Neurofibrillary changes; Diffuse Lewy bodies in the neocortex; Bilateral basal ganglia calcifications.	Unknown.	rs63750048	Coding Exon 5	Point, Missense GCG to GTG	0	Piscopo et al., 2008
V101M	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown.	Unknown; predicted probably damaging in silico.		Coding Exon 5	Point, Missense GTG to ATG	0	Sala Frigerio et al., 2015
K115Efs*	Alzheimer's Disease	AD : Pathogenic	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.		Coding Exon 5	Deletion AAG to A--	0	Jayadev et al., 2010
G117Ter	Alzheimer's Disease	AD : Not Classified	Unknown	Unknown, but in silico prediction of deleteriousness was high (CADD = 40).		Coding Exon 5	Point, Nonsense GGA to TGA	0	Mao et al., 2021
T122P	Alzheimer's Disease	AD : Pathogenic	Unknown.	Increased Aβ42/Aβ40 ratio; increased Aβ42; No change in proteolytic products PSEN2-CTF and PSEN2-NTF.	rs63749851	Coding Exon 6	Point, Missense ACG to CCG	0	Finckh et al., 2000
T122R	Atypical Dementia	Atypical Dementia : Pathogenic	Variable cortical and subcortical atrophy.	Reduced calcium ion released from intracellular stores.	rs28936380	Coding Exon 6	Point, Missense ACG to AGG	0	Binetti et al., 2003
P123L	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown; Neuroimaging showed diffuse cortical atrophy, predominantly in the right hemisphere. FDG-PET showed hypoperfusion in the right temporal and parietal regions.	Unknown; predicted probably damaging in silico.		Coding Exon 6	Point, Missense CCA to CTA	0	Xia et al., 2015
E126fs	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown; neuroimaging showed hippocampal and parahippocampal atrophy.	Unknown; the insertion of one nucleotide (A) is predicted to result in a frameshift at codon 126.		Coding Exon 6	Insertion GAG.GAC to GAA.GGA	0	El Kadmiri et al., 2014
E126K	Alzheimer's Disease	AD : Pathogenic	Unknown.	Unknown; predicted probably damaging in silico.		Coding Exon 6	Point, Missense GAG to AAG	0	Müller et al., 2014
S130L	Alzheimer's Disease, None, Parkinson's Disease Dementia	AD : Unclear Pathogenicity	Neuropathology consistent with AD at autopsy in at least one case. Reduced CSF Aβ43/Aβ40 and Aβ42/Aβ40 ratios in another case, with slightly elevated tau and normal phospho-tau CSF levels.	Decreased Aβ40, Aβ42, Aβ43, sAPPα, sAPPβ, as well as Aβ42/Aβ40 and Aβ43/Aβ40 ratios in CSF of one carrier. However, in transfected cells, unchanged Aβ42/Aβ40 ratio, Aβ42, PSEN2-CTF, and PSEN2-NTF.	rs63750197	Coding Exon 6	Point, Missense TCG to TTG	0	Sorbi et al., 2002; Tedde et al., 2003
V139M	Alzheimer's Disease, None	AD : Unclear Pathogenicity	Bilateral hypoperfusion in the parietal-temporal lobes.	Unknown.		Coding Exon 6	Point, Missense GTG to ATG	0	Bernardi et al., 2008
N141D	Alzheimer's Disease	AD : Pathogenic	Unknown	Unknown, but 3 algorithms predict damaging with a PHRED CADD score of 24.9.		Coding Exon 6	Point, Missense AAC to GAC	0	Wang et al., 2019
N141I (Volga German)	Alzheimer's Disease	AD : Pathogenic	Extensive amyloid plaques; Extensive neurofibrillary tangles (typically a Braak score of V or VI); α-synuclein inclusions, especially in the amygdala; Rare TDP-43 pathology; Hippocampal sclerosis.	Increased Aβ42/Aβ40 ratio; increased Aβ42; No change in proteolytic products PSEN2-CTF and PSEN2-NTF. Altered microglial phenotype.	rs63750215	Coding 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).		Coding Exon 6	Point, Missense AAC to AGC	0	Mao et al., 2021
N141Y	Alzheimer's Disease	AD : Pathogenic	Proband had autopsy-confirmed AD with severe brain atrophy and numerous plaques and neurofibrillary tangles.	Unknown; predicted damaging in silico.	rs61761208	Coding Exon 6	Point, Missense AAC to TAC	0	Niu et al., 2014
L143H	None	AD : Benign	Not applicable.	Unknown.		Coding Exon 6	Point, Missense CTC to CAC	0	Guerreiro et al., 2010
I146T	Alzheimer's Disease	AD : Not Classified	Unknown	Unknown, but predicted damaging in silico (CADD > 20).	rs1215971988	Coding 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).		Coding Exon 6	Point, Missense AGC to AAC	0	Mao et al., 2021
V148I	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown.	Unchanged Aβ42/Aβ40 ratio; unchanged Aβ42; No change in proteolytic products PSEN2-CTF and PSEN2-NTF.	rs63750812	Coding Exon 6	Point, Missense GTC to ATC	0	Lao et al., 1998
I149T	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown	Unknown		Coding Exon 6	Point, Missense ATC to ACC	0	Perrone et al., 2020
V150M	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown	Unknown, but predicted damaging in silico.	rs866044092	Coding Exon 6	Point, Missense GTG to ATG	0	Gao et al., 2019
T153S	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown	Decreased Aβ42 and Aβ43 in CSF of one carrier. Also reduced Aβ40, sAPPα, and sAPPβ.		Coding Exon 6	Point, Missense ACC to AGC	0	Perrone et al., 2020
K161R	Alzheimer's Disease	AD : Pathogenic	Unknown.	Unknown.		Coding Exon 6	Point, Missense AAG to AGG	0	Wallon et al., 2012
R163C	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown	Unknown, but predicted damaging by in silico algorithms.	rs200931244	Coding Exon 6	Point, Missense CGC to TGC	0	Gao et al., 2019
R163H	None	AD : Benign	Not applicable.	Unknown.	rs778936527	Coding Exon 6	Point, Missense CGC to CAC	0	Puschmann et al., 2009
H169N	Alzheimer's Disease, Frontotemporal Dementia, Progressive Nonfluent Aphasia	AD : Unclear Pathogenicity, FTD : Unclear Pathogenicity	Unknown; neuroimaging showed mild atrophy and widespread hypometabolism. PIB-PET showed amyloid deposition in the AD case, but no amyloid deposition in the FTD case.	Unknown.		Coding Exon 7	Point, Missense CAT to AAT	0	Shi et al., 2015
M174I	Alzheimer's Disease	AD : Not Classified	Neuropathology consistent with AD.	Unknown, but in silico algorithm predicted damaging (PHRED-scaled CADD > 20).		Coding Exon 7	Point, Missense ATG to ATA	0	Wong et al., 2019
M174V	Alzheimer's Disease, Frontotemporal Dementia	AD : Benign	Unknown; imaging has shown frontal atrophy and hypoperfusion in temporoparietal regions.	Unknown; predicted benign in silico.	rs61757781	Coding Exon 7	Point, Missense ATG to GTG	0	Andreoli et al., 2008; Clarimón et al., 2008; Guerreiro et al., 2010
S175C	Alzheimer's Disease	AD : Pathogenic	Unknown; MRI showed focal atrophy in the medial temporal lobe; SPECT showed bilateral hypoperfusion in temporoparietal regions.	Unknown.	rs775145486	Coding Exon 7	Point, Missense TCT to TGT	0	Piscopo et al., 2010
S175F	Alzheimer's Disease	AD : Pathogenic	Unknown, but in one case brain imaging showed atrophy and hypometabolism consistent with AD.	Unknown, but multiple in silico algorithms suggest it is damaging.		Coding Exon 7	Point, Missense TCT to TTT	0	Guven et al., 2021
F183S	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown.	Unknown		Coding Exon 7	Point, Missense TTC to TCC	0	Wojtas et al., 2012
G212V	Alzheimer's Disease	AD : Pathogenic	Neuropathology consistent with AD.	Unknown; predicted pathogenic in silico.		Coding Exon 8	Point, Missense GGG to GTG	0	Marín-Muñoz et al., 2016
V214L	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown; neuroimaging showed diffuse cortical atrophy and widespread hypometabolism.	Unknown; structural changes were predicted in silico, especially at amino acids 214, 219, and 220. PolyPhen2 predicted a probably or possibly damaging effect.		Coding Exon 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).		Coding Exon 8	Point, Missense CAC to TAC	0	Mao et al., 2021
Q228L	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown.	Unknown.	rs63750880	Coding Exon 8	Point, Missense CAG to CTG	0	Zekanowski et al., 2003
Y231C	Frontotemporal Dementia	FTD : Pathogenic	Unknown; MRI showed diffuse subcortical and cortical atrophy, particularly in the frontotemporoparietal lobes.	Unknown.		Coding Exon 8	Point, Missense TAC to TGC	0	Marcon et al., 2009
I235F	Alzheimer's Disease, None	AD : Unclear Pathogenicity	Unknown.	Increased Aβ42/Aβ40 ratio in cells.		Coding Exon 8	Point, Missense ATC to TTC	0	Lee et al., 2014
S236S		AD : Unclear Pathogenicity	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.	rs61730652	Coding Exon 8	Point, Silent AGT to AGC	0	Coppola et al., 2020
A237V	Alzheimer's Disease	AD : Unclear Pathogenicity	Neuropathology consistent with AD.	Unknown; predicted possibly damaging in silico.	rs200670135	Coding Exon 8	Point, Missense GCG to GTG	0	Sassi et al., 2014
L238F	Alzheimer's Disease	AD : Pathogenic	Unknown.	Increased Aβ42/Aβ40 ratio in cellular assay.		Coding Exon 8	Point, Missense CTC to TTC	0	Sala Frigerio et al., 2015
L238P	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown; MRI showed supratentorial cortical atrophy, particularly atrophy of the parietal cortex.	Unknown; predicted damaging in silico.		Coding Exon 8	Point, Missense CTC to CCC	0	Blauwendraat et al., 2016
M239I	Alzheimer's Disease	AD : Pathogenic	Moderate cortical atrophy; Numerous neurofibrillary tangles; Numerous senile plaques, especially in the amygdala.	Increased Aβ42/Aβ40 ratio; increased Aβ42; No change in proteolytic products PSEN2-CTF and PSEN2-NTF; Reduced calcium release.	rs63749884	Coding Exon 8	Point, Missense ATG to ATA	0	Finckh et al., 2000
M239T	Alzheimer's Disease	AD : Unclear Pathogenicity	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).		Coding Exon 8	Point, Missense ATG to ACG	0	Li et al., 2021; Jiao et al., 2021; Mao et al., 2021
M239V	Alzheimer's Disease	AD : Pathogenic	Diffuse cerebral atrophy; Senile plaques; Neurofibrillary tangles (stage VI of Braak and Braak); Ectopic neurons in the subcortical white matter; Extracellular "ghost" neurofibrillary tangles.	Increased Aβ42/Aβ40 ratio; increased Aβ42; No change in proteolytic products PSEN2-CTF and PSEN2-NTF.	rs28936379	Coding Exon 8	Point, Missense ATG to GTG	0	Rogaev et al., 1995
A252T	None	AD : Benign	Not applicable.	Decreased Aβ42 and Aβ40 in cells, without altering Aβ42/Aβ40 ratio.	rs138836272	Coding Exon 8	Point, Missense GCG to ACG	0	Guerreiro et al., 2010
A258T	None	AD : Benign	Not applicable.	Unknown.	rs148238688	Coding Exon 8	Point, Missense GCC to ACC	0	Sala Frigerio et al., 2015
A258V	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown	Predicted not pathogenic in silico.	rs14443227784	Coding Exon 8	Point, Missense GCC to GTC	0	Yagi et al., 2014
R284G		AD : Pathogenic	Unknown.	Increased Aβ42 and Aβ42/Aβ40 in a cell assay.	rs1208742830	Coding Exon 9	Point, Missense AGA to GGA	0	Hsu et al., 2018
P287P		AD : Unclear Pathogenicity	Unknown, but associated with increased glucose metabolism in the bilateral fronto-temporo-parietal cortices.	Unknown.	rs75733498	Coding Exon 9	Point, Silent CCC to CCT	0	Seo et al., 2020
M298T	Alzheimer's Disease	AD : Uncertain Significance	Unknown.	Unknown. Some, but not all, in silico algorithms predicted damaging (PHRED-scaled CADD>20).	rs1482790603	Coding Exon 10	Point, Missense ATG to ACG	0	Wang et al., 2019
T301M	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown.	Unchanged Aβ42/Aβ40 ratio.	rs144277432	Coding Exon 10	Point, Missense ACG to ATG	0	Croes et al., 2004
K306fs	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown; neuroimaging showed cortical atrophy.	Unknown; the deletion of a single nucleotide (A) in exon 9 is predicted to result in a frameshift at codon 306.		Coding Exon 10	Deletion AAG.CTG to AGC.TGG	0	El Kadmiri et al., 2014
P334A	Alzheimer's Disease, None	AD : Benign	Not applicable.	Unknown.		Coding Exon 11	Point, Missense CCT to GCT	0	Lee et al., 2014
P334R	Alzheimer's Disease, None	AD : Benign	Not applicable.	Unknown.	rs63750207	Coding Exon 11	Point, Missense CCT to CGT	0	Lleó et al., 2002
P348L	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown.	Decreased Aβ40; increased Aβ42/Aβ40 ratio in cell assay.		Coding Exon 11	Point, Missense CCA to CTA	0	Blauwendraat et al., 2016
I368F	Alzheimer's Disease	AD : Not Classified	Unknown	Unknown, but multiple in silico algorithms predicted a damaging effect (PHRED-scaled CADD >20).		Coding 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)		Coding Exon 12	Point, Missense TTC to TCC	0	Wan et al., 2021
A377V	Alzheimer's Disease, None	AD : Benign	Not applicable.	Unknown.		Coding Exon 12	Point, Missense GCG to GTG	0	Lee et al., 2014
A379D	Alzheimer's Disease	AD : Pathogenic	Unknown	Unknown, but predicted damaging in silico. PHREDD CADD score = 27.1		Coding Exon 12	Point, Missense GCC to GAC	0	Wang et al., 2019
V393M	Alzheimer's Disease	AD : Unclear Pathogenicity	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	Coding Exon 12	Point, Missense GTG to ATG	0	Lindquist et al., 2008
A394Pfs*8	Alzheimer's Disease	AD : Not Classified	Unknown	Unknown		Coding 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).		Coding Exon 13	Point, Missense GCC to TCC	0	Wong et al., 2019
T421M	Alzheimer's Disease	AD : Pathogenic	Unknown	Predicted to be pathogenic in silico (SIFT, PolyPhen2, Pmut).	rs756609078	Coding Exon 13	Point, Missense ACG to ATG	0	Yagi et al., 2014
T430M	Alzheimer's Disease	AD : Unclear Pathogenicity	Right frontotemporal hypoperfusion.	Unknown.	rs63750666	Coding Exon 13	Point, Missense ACG to ATG	0	Ezquerra et al., 2003
P436L	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown, but MRI of one carrier showed bilateral atrophy of the temporal lobe and hippocampus.	Unknown.		Coding Exon 13	Point, Missense CCG to CTG	0	Han et al., 2020
D439A	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown; imaging showed moderate cortical atrophy in the frontal and parietal regions.	MIxed results in vitro.	rs63750110	Coding Exon 13	Point, Missense GAC to GCC	0	Lleó et al., 2001
G359Lfs*74 (Intron 11 delA)	Alzheimer's Disease, Mild Cognitive Impairment	AD : Unclear Pathogenicity, MCI : Unclear Pathogenicity	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.		Both Intron 11	Point	0	Perrone et al., 2018
G359Lfs*74 (Intron 11 delAG)	Amyotrophic Lateral Sclerosis	ALS : Unclear Pathogenicity	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.		Both Intron 11	Deletion	0	Perrone et al., 2018
c.887-3C>T (rs1230394996)	Alzheimer's Disease	AD : Unclear Pathogenicity	Unknown	Unknown. PHRED CADD score of 9.977.	rs1230394996	Non-Coding Intron 9	Point	0	Wang et al., 2019

Mutations

PSEN-2

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PSEN2 (80)