ClinVar Genomic variation as it relates to human health

The c.584T>C is a missense variant predicted to cause a substitution of methionine by threonine at amino acid 195 (p.Met195Thr). The highest population minor allele frequency in gnomAD v4.1.0 is 0.0022% (4/60018, CI 95%) in the Admixed American population (PM2_Supporting). The c.584T>C variant has been detected in trans with c.35delG in one individual with moderate-severe hearing loss (PMID: 19235794). The computational predictor REVEL gives a score of 0.968 which is above the threshold of 0.7, evidence that correlates with impact to GJB2 function (PP3). Another missense variant c.583G>C (p.Met195Val; ClinVar Variation ID: 22537) in the same codon has been classified as pathogenic for hearing loss by the ClinGen Hearing Loss VCEP (PM5). Analysis in Hela cells demonstrated that the CX26-p.Met195Thr protein formed a gap junction but with significantly decreased dye transfer. Additionally, electrophysiological characterization of the mutant in Xenopus oocytes resulted in a completely non-functional channel (PS3_Moderate; PMID: 23967136). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive non-syndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (PM2_Supporting, PP3, PM3, PM5, PS3_Moderate; Version 2; 5/15/24).

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 195 of the GJB2 protein (p.Met195Thr). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of autosomal recessive deafness (PMID: 19235794, 20233142). ClinVar contains an entry for this variant (Variation ID: 438620). 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%. Experimental studies have shown that this missense change affects GJB2 function (PMID: 23967136). 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.

Variant summary: GJB2 c.584T>C (p.Met195Thr) results in a non-conservative amino acid change located in the Gap junction protein, cysteine-rich domain (IPR019570) of the encoded protein sequence. This alters a highly conserved residue in which other missense variants have been found in association with hearing loss (HGMD). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251352 control chromosomes (gnomAD). c.584T>C has been reported in the literature in individuals affected with Non-Syndromic Hearing Loss without strong evidence of causality (Lee_2009, Chinetti_2010). These reports do not provide unequivocal conclusions about association of the variant with Non-Syndromic Hearing Loss. At least one publication reports experimental evidence evaluating an impact on protein function, funding no impact on gap junction formation or stability but substantially reduced function (Ambrosi_2013). The following publications have been ascertained in the context of this evaluation (PMID: 19235794, 23967136, 20233142). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=2) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.