ClinVar

Description

The GJB2 c.551G>A; p.Arg184Gln variant (rs80338950) is reported in the literature in multiple individuals affected with autosomal dominant nonsyndromic hearing loss (Amritkumar 2018, Hamelmann 2001, Wang 2002), including several confirmed de novo cases (Huang 2011, Pang 2014). Functional analyses of the variant protein show a dominant negative effect on both connexin 26 and connexin 30 in vitro (Su 2010, Yum 2010, Zhang 2011). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 29662), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 184 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. References: Amritkumar P et al. Role of DFNB1 mutations in hereditary hearing loss among assortative mating hearing impaired families from South India. BMC Med Genet. 2018 Jun 19;19(1):105. Hamelmann C Pattern of connexin 26 (GJB2) mutations causing sensorineural hearing impairment in Ghana. Hum Mutat. 2001;18(1):84-5. Huang S et al. De novo dominant mutation of GJB2 in two Chinese families with nonsyndromic hearing loss. Int J Pediatr Otorhinolaryngol. 2011 Oct;75(10):1333-6. Pang X et al. Characterization of spectrum, de novo rate and genotype-phenotype correlation of dominant GJB2 mutations in Chinese hans. PLoS One. 2014 Jun 19;9(6):e100483. Su CC et al. Mutation R184Q of connexin 26 in hearing loss patients has a dominant-negative effect on connexin 26 and connexin 30. Eur J Hum Genet. 2010 Sep;18(9):1061-4. Wang YC et al. Mutations of Cx26 gene (GJB2) for prelingual deafness in Taiwan. Eur J Hum Genet. 2002 Aug;10(8):495-8. Yum SW et al. Dominant connexin26 mutants associated with human hearing loss have trans-dominant effects on connexin30. Neurobiol Dis. 2010 May;38(2):226-36. Zhang J et al. Dominant Cx26 mutants associated with hearing loss have dominant-negative effects on wild type Cx26. Mol Cell Neurosci. 2011 Jun;47(2):71-8.