ClinVar

Description

Across a selection of the available literature, the GJB2 c.257C>G (p.Thr86Arg) missense variant, which has been found mainly in the East Asian population, was identified in a homozygous state in at least one individual with autosomal recessive nonsyndromic hearing loss and in a compound heterozygous state in at least four unrelated individuals, also with autosomal recessive nonsyndromic hearing loss (Ohtsuka et al. 2003; Choi et al. 2009; Shi et al. 2016; Sakuma et al. 2016; Zhang et al. 2016). Huang et al. (2013) further identified one patient with profound bilateral sensorineural hearing loss and enlarged vestibular aqueduct with double biallelic variants in the GJB2 and SLC26A4 genes; the patient was compound heterozygous for the p.Thr86Arg variant and a pathogenic frameshift variant common in the East Asian population. The p.Thr86Arg variant was absent from 247 controls but is reported at a frequency of 0.00006 in the East Asian population of the Genome Aggregation Database, based on one allele in a region of good sequence coverage so the variant is presumed to be rare. HEK293 cells transfected with the variant protein demonstrated that the p.Thr86Arg variant led to defective intercellular trafficking and oligomerization of the protein (Choi et al. 2009). Co-transfection with the wild type channel demonstrated that the p.Thr86Arg variant did not affect ionic transfer and biochemical coupling, consistent with the recessive nature of the variant. Based on the collective evidence, the p.Thr86Arg variant is classified as pathogenic for autosomal recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.