ClinVar

Description

The NM_004004.6(GJB2):c.563A>G variant in GJB2 is a missense variant predicted to cause substitution of lysine by arginine at amino acid 188 (p.Lys188Arg). The highest population minor allele frequency of the variant is 0.00025% (3/1180000) in the European (non-Finnish) population in gnomAD v.4.0.0 (PM2_Supporting). This variant has been reported in at least three probands with hearing loss (2.5 PM3_Strong points). Two probands were compound heterozygous (one confirmed trans, the other one assumed trans) with the pathogenic c.35delG, p.G12Vfs variant (Clinvar ID: 17004, PMID 17666888, internal data from GeneDx). Another proband was compound heterozygous for the pathogenic variant p.Leu90Pro (ClinVar ID: 17016, University of Minnesota internal data). The REVEL computational prediction analysis tool produced a score of 0.9 meeting PP3. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PM2_Supporting, PM3_Strong, PP3 (VCEP specifications version 2; 01.17.2024).