ClinVar

Description

The GJB2 c.250G>T; p.Val84Leu variant (rs104894409), as well as another variant generating the same amino acid substitution (c.250G>C; p.Val84Leu), are reported in the literature in multiple individuals affected with nonsyndromic hearing loss (NSHL) (Cryns 2004, Snoeckx 2005), including individuals also carrying the pathogenic c.35delG variant (Putcha 2007). The c.250G>T; p.Val84Leu variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 167134), and is only observed on four alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The valine at codon 84 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional tests indicate that, while the variant protein can form functional channels capable of electrical coupling (Ambrosi 2010, Bruzzone 2003), the p.Val84Leu substitution results in reduced permeability to inositol 1,4,5-trisphosphate (Beltramello 2005). Based on available information, this variant is considered to be pathogenic. References: Ambrosi et al. Analysis of four connexin26 mutant gap junctions and hemichannels reveals variations in hexamer stability. Biophys J. 2010 98(9): 1809-1819. Beltramello et al. Impaired permeability to Ins(1,4,5)P3 in a mutant connexin underlies recessive hereditary deafness. Nat Cell Biol. 2005 7(1):63-69. Bruzzone et al. Loss-of-function and residual channel activity of connexin26 mutations associated with non-syndromic deafness. FEBS Lett. 2003 533(1-3): 79-88. Cryns et al. A genotype-phenotype correlation for GJB2 (connexin 26) deafness. J Med Genet. 2004 41(3): 147-154. Putcha et al. A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort. Genet Med. 2007 9(7): 413-426. Snoeckx et al. GJB2 mutations and degree of hearing loss: a multicenter study. Am J Hum Genet. 2005 77(6): 945-957.