ClinVar

Description

Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the c.224G>A, p.Arg75Gln variant is absent from population databases (gnomAD, GO-ESP, 1000 genomes) meeting PM2 criteria. This variant has been found in 6 families (2 familial cases with dominant hearing loss and palmoplantar keratoderma and 4 families with non-syndromic autosomal dominant hearing loss) and segregated it correctley in all members of the families, meeting PS4_Mod and PP1_Mod (PMID: 12372058, 15790391, 15996214, 16059934,23451214). A previous variant (p.Arg75Trp) has been previously described as causative mutation of syndromic (palmoplantar keratoderma and autosomal dominant hearing loss) and non-syndromic autosomal dominant hearing loss, applying to PM5 rule. Computational evidence predicted the mutation to be damaging to the protein (REVEL= 0.985; PP3). Functional studies in HeLa cells demonstrated that p.Arg75Gln mutant did not present dye transfer (Lucifer Yellow, Neurobiotin and calcein dyes) and showed a dominant effect when it was co-expressed with wtCX26. Besides there was a null electrical coupling (PMID: 15996214, 2104787). In addition to his, it was demonstrated a partial inhibition of neurobiotin when it was co-expressed with wtCX30 applying to PS3_Moderate rule. Therefore, the c.224G>A variant meets criteria to be classified as pathogenic for autosomal dominant non-syndromic hearing loss and syndromic hearing loss (palmoplantar keratoderma and deafness): PM2, PS4_Moderate, PP1_Moderate, PM5, PP3 and PS3_Moderate.