ClinVar

Description

Variant summary: GJB2 c.487A>G (p.Met163Val) results in a conservative amino acid change located in the extracellular 2 domain (Tang_2006) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 251140 control chromosomes, predominantly at a frequency of 0.00075 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 2.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in GJB2 causing Non-Syndromic Hearing Loss phenotype (0.00034), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.487A>G has been reported in the literature as a VUS with a non-informative genotype (i.e., second allele not specified or heterozygous) for a recessive mode of inheritance among individuals with various forms of moderate non sensorineural hearing loss undergoing genetic evaluation in small and large sized gene panels for hearing loss (example, Marlin_2001, Janecke_2002, Bayazit_2003, Tang_2006, Hamid_2009, Padma_2009, Bonyadi_2009, Yilmaz_2010, Al-Qahtani_2010, Mahdieh_2011, Falah_2012, Leone_2017, Buonfiglio_2020, Xie_2021). At-least one individual with moderate hearing loss reported a homozygous genotype although no family history, co-segregation/co-occurrence was specified (Amorini_2015). One family where the variant was transmitted from a father with late onset hearing impairment to two affected siblings with early onset hearing loss reported a possible instance of autosomal dominant transmission with anticipation (Falah_2012). Another report speculates a role in digenic inheritance with synergistic heterozygosity for this variant and variants in the TMPRSS3 gene (Leone_2017). However, a firm conclusion regarding these atypical modes of inheritance remain speculative. These data indicate that the variant may be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function (example, Bruzzone_2003, Press_2017). The most pronounced variant effect results in a complete inability to form homotypic channels since the level of junctional conductance measured never exceeded background values (Bruzzone_2003) and impaired gap junction function (Press_2017). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a predominant consensus as VUS (n=6) (likely pathogenic, n=1). Some submitters cite overlapping evidence utilized in the context of this evaluation and the prevailing interpretation even in most recent publications remains as VUS (example, Buonfiglio_2020). Based on the evidence outlined above, the variant was classified as uncertain significance.