ClinVar

Description

The p.Met93Ile variant in GJB2 has been reported in at least 8 individuals with hearing loss including four compound heterozygotes with pathogenic variants in t rans (Wu 2002, Cryns 2004, Najmabadi 2005, Snoeckx 2005, Putcha 2007, Naghavi 20 08, Rodriguez-Paris 2010, Tsukada 2010, LMM data). (Wu 2002, Cryns 2004, Tsukada 2010). The hearing loss described in these four individuals ranged from mild t o moderately-severe (Wu 2002, Cryns 2004, Tsukada 2010, LMM data). This variant has also been identified in 4/126570 European chromosomes by the Genome Aggregat ion Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs397516871). Alth ough this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency for nonsyndromic hear ing loss. Computational prediction tools and conservation analysis suggest that the variant may impact the protein, though this information is not predictive en ough to determine pathogenicity. In summary, although additional studies are req uired to fully establish its clinical significance, the p.Met93Ile variant is li kely pathogenic based on compound heterozygosity in multiple affected individual s.