Submissions for variant NM_000021.4(PSEN1):c.236C>T (p.Ala79Val)

gnomAD frequency: 0.00004  dbSNP: rs63749824

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000529477	SCV000639604	pathogenic	Alzheimer disease 3; Frontotemporal dementia; Pick disease; Acne inversa, familial, 3	2025-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 79 of the PSEN1 protein (p.Ala79Val). This variant is present in population databases (rs63749824, gnomAD 0.004%). This missense change has been observed in individuals with early-onset Alzheimer's disease and late-onset Alzheimer's disease (PMID: 9384602, 10631141, 27454811). It has also been observed to segregate with disease in related individuals. Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this PSEN1 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 18,931 individuals referred to our laboratory for PSEN1 testing. ClinVar contains an entry for this variant (Variation ID: 18157). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PSEN1 protein function with a positive predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PSEN1 function (PMID: 17366635, 17431506). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics	RCV000084281	SCV000843412	pathogenic	not provided	2023-06-07	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant is statistically more frequent in individuals affected with Alzheimer disease than in the general population and/or healthy controls. This variant associates with Alzheimer disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies show that this variant results in an increase in AB42/AB40 ratios (PMID: 17366635, 16752394).
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV005234786	SCV005882840	pathogenic	Dementia	2024-08-05	criteria provided, single submitter	clinical testing	PS3 (PMID: 17366635, 16752394), PS4 (PMID: 30797548, 30924900, 9384602, 10631141, 27454811), PP1 (PMID 27454811), PP3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000019787	SCV005885230	pathogenic	Alzheimer disease 3	2025-02-24	criteria provided, single submitter	clinical testing	Variant summary: PSEN1 c.236C>T (p.Ala79Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251430 control chromosomes. c.236C>T has been reported in the literature in multiple individuals affected with Alzheimer Disease (e.g., Cruts_1998, Day_2016, Finckh_2000). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 9384602, 27454811, 10631141). ClinVar contains an entry for this variant (Variation ID: 18157). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000019787	SCV000040085	pathogenic	Alzheimer disease 3	2007-05-01	no assertion criteria provided	literature only
GeneReviews	RCV000019787	SCV000040382	not provided	Alzheimer disease 3		no assertion provided	literature only
VIB Department of Molecular Genetics, University of Antwerp	RCV000084281	SCV000116417	not provided	not provided		no assertion provided	not provided