Submissions for variant NM_000021.4(PSEN1):c.485T>G (p.Ile162Ser)

dbSNP: rs1898533739

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001070299	SCV001235521	uncertain significance	Alzheimer disease 3; Frontotemporal dementia; Pick disease; Acne inversa, familial, 3	2019-12-19	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine with serine at codon 162 of the PSEN1 protein (p.Ile162Ser). The isoleucine residue is highly conserved and there is a large physicochemical difference between isoleucine and serine. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with PSEN1-related conditions. This variant is not present in population databases (ExAC no frequency).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317428	SCV004020350	uncertain significance	not specified	2023-06-01	criteria provided, single submitter	clinical testing	Variant summary: PSEN1 c.485T>G (p.Ile162Ser) results in a non-conservative amino acid change located in the Presenilin/signal peptide peptidase domain (IPR006639) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251374 control chromosomes. c.485T>G has been reported in the literature in at-least two reportedly symptomatic individuals affected with features of Alzheimer Disease and authors weighting co-segregation with disease in multiple affected family members as an evidence criterion (ACMG PP1) in their final classification as definetely pathogenic (Acosta-Uribe_2022). However, the details and/or extent of co-segregation is not reported. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 35260199). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance citing absence in literature. Based on the evidence outlined above, until additional clinical and functional studies are reported, the variant was classified as VUS-possibly pathogenic.