ClinVar

Description

This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 417 of the RPE65 protein (p.Glu417Gln). This variant is present in population databases (rs62636299, gnomAD 0.0009%). This missense change has been observed in individual(s) with autosomal recessive Leber congenital amaurosis (PMID: 11462243). ClinVar contains an entry for this variant (Variation ID: 98835). 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 RPE65 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects RPE65 function (PMID: 16150724, 20043869, 24849605, 26427455). This variant disrupts the p.Glu417 amino acid residue in RPE65. Other variant(s) that disrupt this residue have been observed in individuals with RPE65-related conditions (PMID: 11462243, 31630094), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.