ClinVar

Description

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 381 of the PSEN1 protein (p.Leu381Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of early-onset Alzheimer disease (PMID: 24121961; Invitae). ClinVar contains an entry for this variant (Variation ID: 120170). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PSEN1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PSEN1 function (PMID: 35365805). This variant disrupts the p.Leu381 amino acid residue in PSEN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27930341, 34776449). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.