ClinVar

Description

This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 195 of the GJB2 protein (p.Met195Ile). This variant is present in population databases (rs570552952, gnomAD 0.0009%). This missense change has been observed in individual(s) with autosomal recessive non-syndromic deafness (PMID: 29148562). This variant has been reported in individual(s) with clinical features of autosomal dominant non-syndromic deafness (PMID: 18941476, 20601923); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 1479826). 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 GJB2 protein function with a positive predictive value of 95%. This variant disrupts the p.Met195 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20497192, 24013081, 30146550, 33597575). 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.