ClinVar

Description

Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the filter allele frequency of c.478G>A, p.(Gly160Ser) is 0,17% (55/24922 African alleles 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 BS1_Supporting criteria. Computational analysis predicted a damage impact of the mutation to the protein (REVELscore:0.767) meeting PP3 rule. The p.(Gly160Ser) change has been identified in heterozygous state in several hearing loss individuals among different ethnic groups (PMID: 24158611, 21162657, 24529908, 19371219, 19125024, 17660464, 16222667, 15070423). This variant has been found in two Austrian familial cases which have been tested only for GJB2 gene: the first case with both parents and child affected in which the proband and her father carried the variant in heterozygous state. The second case is composed of three affected family members: mother and her two daughters. The mother carried p.(Gly160Ser) and her two daughters were not available for the study (PMID: 12189487). Hence, the evidence provided was not enough to apply PP1 rule and was not counted. Besides, this variant has been found in cis with a known pathogenic variant in two unrelated patients (PMID: 22103400) meeting BP2 criteria. Finally, p.(Gly160Ser) change was found with p.Val37Ile and c.35delG in two patients but phase unknown applying to PM3 rule. In summary, this variant meets criteria to be classified as likely benign for autosomal recessive non-syndromic hearing loss (BS1_Supporting, PP3, BP2 and PM3)