Submissions for variant NM_000021.4(PSEN1):c.786G>C (p.Leu262Phe)

dbSNP: rs63750248

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000084367	SCV001145227	likely pathogenic	not provided	2018-11-26	criteria provided, single submitter	clinical testing	Not found in the total gnomAD dataset, and the data is high quality (0/281164 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Damaging to protein function(s) relevant to disease mechanism.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV004783741	SCV005395964	pathogenic	Alzheimer disease 3	2024-11-13	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV005222748	SCV005863534	pathogenic	Alzheimer disease 3; Frontotemporal dementia; Pick disease; Acne inversa, familial, 3	2024-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 262 of the PSEN1 protein (p.Leu262Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Alzheimer's disease (PMID: 9347932, 35650585). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 98077). 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 have shown that this missense change affects PSEN1 function (PMID: 27930341). This variant disrupts the p.Leu262 amino acid residue in PSEN1. Other variant(s) that disrupt this residue have been observed in individuals with PSEN1-related conditions (PMID: 22503161), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
VIB Department of Molecular Genetics, University of Antwerp	RCV000084367	SCV000116503	not provided	not provided		no assertion provided	not provided
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000084367	SCV001808129	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000084367	SCV001964628	pathogenic	not provided		no assertion criteria provided	clinical testing