ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.193T>C (p.Tyr65His) (rs886037849)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000821 SCV001157886 likely pathogenic not specified 2018-09-21 criteria provided, single submitter clinical testing The GJB2 c.193T>C; p.Tyr65His variant (rs111033203), is reported in the literature in at least one individual affected with severe Vohwinkel syndrome and congenital sensory hearing impairment (de Zwart-Storm 2011). This variant is reported in ClinVar (Variation ID: 253134), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The tyrosine at codon 65 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, another variant at this codon (c.194A>G, p.Tyr65Cys) has been reported in at least one individual with sensorineural hearing loss (Tayoun 2016). Codon 65 is located in the first extracellular domain of the protein, in which variants associated with autosomal dominant syndromic or nonsyndromic hearing loss cluster (Iossa 2011). In vitro functional analyses demonstrate mislocalization of the p.Tyr65His variant protein and reduced cellular gap junction function (de Zwart-Storm 2011). Based on available information, the p.Tyr65His variant is considered to be likely pathogenic. References: de Zwart-Storm EA et al. A novel missense mutation in GJB2, p.Tyr65His, causes severe Vohwinkel syndrome. Br J Dermatol. 2011 Jan;164(1):197-9. Iossa S et al. GJB2 Gene Mutations in Syndromic Skin Diseases with Sensorineural Hearing Loss. Curr Genomics. 2011 Nov;12(7):475-785. Tayoun AN et al. Targeted Droplet-Digital PCR as a Tool for Novel Deletion Discovery at the DFNB1 Locus. Hum Mutat. 2016 Jan;37(1):119-26.
OMIM RCV000239514 SCV000297932 pathogenic Mutilating keratoderma 1997-11-01 no assertion criteria provided literature only

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