ClinVar

Description

The GJB2 c.167delT (p.Leu56ArgfsTer26) variant results in a frameshift and is predicted to result in premature truncation of the protein. The p.Leu56ArgfsTer26 variant is a well-known variant that is common in the Ashkenazi Jewish population, where the carrier rate is as high as 7.5% (Lerer et al. 2000). Across a selection of the available literature, the p.Leu56ArgfsTer26 variant has been identified in a total of 34 patients with autosomal recessive nonsyndromic hearing loss, including in 16 in a homozygous state, in 15 in a compound heterozygous state, and in three in a heterozygous state (Zelante et al. 1997; Morell et al. 1998; Lerer et al. 2000; Batissoco et al. 2009; Bonyadi et al. 2014; Amorini et al. 2015). The p.Leu56ArgfsTer26 variant was shown to segregate with disease in at least one family. Patients with this variant show a spectrum of phenotypic manifestation from mild to profound hearing loss, even among affected family members (Morell et al. 1998). Control data is unavailable for this variant, which is reported at a frequency of 0.00145 in the European-American population of the Exome Sequencing Project (Morell et al. 1998; Lerer et al. 2000). Based on the collective evidence and the potential impact of frameshift variants, the p.Leu56ArgfsTer26 variant is classified as pathogenic for GJB2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.