ClinVar Genomic variation as it relates to human health

The NM_004004.5(GJB2):c.550C>T missense variant identified in exon 2 of GJB2, is predicted to create a major amino acid change from an arginine to a tryptophan at amino acid position 184, NP_003995.2(GJB2):p.(Arg184Trp). The arginine at this position has high conservation (100 vertebrates, UCSC). In silico software predicts this variant to be disease causing. It is situated within the cysteine rich domain of theGJB2 protein. This variant has been observed in a population database at a frequency of 0.00001% (ExAC, GnomAD). This variant has been reported as a pathogenic variant in multiple patients with hearing loss (Deafness variation database, The Connexin-deafness homepage). Based on current information and in association with the NM_004004.5(GJB2):c.101T>C missense variant, this variant has been classified as PATHOGENIC. The presence of these two variants suggests a possible compound heterozygous mode of inheritance which is consistent with autosomal recessive deafness.

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10830906, 25388846, 21728791, 16380907, 26096904, 20650534, 31827275)

This variant disrupts the p.Arg184 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10874298, 12176036, 12189493, 12505163, 15241677, 18941476, 19371219, 25708704, 26117665). 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. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GJB2 protein function. ClinVar contains an entry for this variant (Variation ID: 560669). This missense change has been observed in individuals with autosomal recessive nonsyndromic deafness (PMID: 14985372, 20650534, 30068397). This variant is present in population databases (no rsID available, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 184 of the GJB2 protein (p.Arg184Trp).

Arg184Trp variant in GJB2 has been found in a Chinese family with autosomal recessive inheritance hearing loss, segregated with the disease in the family members. The proband was homozygous of this mutation and the parents carried this variant equally. The proband has bilateral profound hearing loss and the parents have normal hearing .