ClinVar

Description

ClinVar contains an entry for this variant (Variation ID: 217161). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 376 of the MFN2 protein (p.Met376Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant Charcot-Marie-Tooth disease (PMID: 19889647, 22492563, 22851605, 22926664, 24473995, 26801520, 28251916). 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 MFN2 protein function. This variant disrupts the p.Met376 amino acid residue in MFN2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24957169). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.