ClinVar

Description

Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the filter allele frequency of c.380G>A, p.Arg127His variant in GJB2 gene is 9.5% (3021/30612 South Asian chromosomes with 95% CI) from Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which meets the threshold to apply for BA1 rule. Computational evidence was not enough to neither apply to PP3 nor BP4 since REVEL score was 0.387. This variant has been identified in trans with pathogenic variants in control subjects meeting BS2 rule (PMID: 11493200, 15070423, 12746422). It was shown in some familial cases that different genotypes composed of p.Arg127His change in homozygous state and in compound heterozygous with pathogenic variants did not segregate within the members of those families applying to BS4 criteria (PMID:19929408). On the other hand, this variant has been detected in trans with pathogenic variants in at least for patients with hearing loss (PMID: 16380907, 12746422, 19366456, 19929408). However, since this genetic variant presents a high allele frequency in general population, the PM3 rule was downgraded to supporting strength (PM3_Supporting). Functional studies (dye transfer assay and electrophysiological records) in HeLa cells and Xenopus Laevis oocytes presented contradictory results, so that evidence was not counted (PMID: 12176036, 16300957, 12189493, 12562518). In summary, this variant meets criteria to be classified as benign for autosomal recessive non-syndromic hearing loss: BA1, BS2, BS4, PM3_Supporting.