ClinVar

Description

The p.Val91fs (c.269_270insT) variant in GJB2 has been reported in over 10 indiv iduals with hearing loss who were homozygous or compound heterozygous for a know n pathogenic variant (Dahl 2013, Dalamon 2013, Denoyelle 1999, Gravina 2010, Gre en 1999, Pandya 2003, Preciado 2004, Propst 2006, Siem 2010, Snoeckx 2005). Thi s variant has been identified in 2/66710 of European chromosomes by the Exome Ag gregation Consortium (ExAC, http://exac.broadinstitute.org); though this frequen cy is low enough to be consistent with a recessive carrier frequency. This varia nt is predicted to cause a frameshift, which alters the protein?s amino acid seq uence beginning at position 91 and leads to a premature termination codon 11 ami no acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the GJB2 gene is an establish ed disease mechanism in autosomal recessive sensorineural hearing loss. In summ ary, this variant meets criteria to be classified as pathogenic for autosomal re cessive hearing loss based on predicted impact to the protein and prior reports of the variant in trans with a known pathogenic variant. ACMG/AMP Criteria appli ed: PVS1, PM3_VeryStrong, PM2.