ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.250G>T (p.Val84Leu) (rs104894409)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000790715 SCV000227309 pathogenic not provided 2014-02-24 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000505951 SCV000603824 pathogenic not specified 2019-05-30 criteria provided, single submitter clinical testing 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.
Invitae RCV000790715 SCV000958454 pathogenic not provided 2019-10-25 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 84 of the GJB2 protein (p.Val84Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. This variant is present in population databases (rs104894409, ExAC 0.009%). This missense change has been observed to be homozygous or in combination with another GJB2 variant in individuals affected with deafness (PMID: 16380907, 26346709, 24013081, 19235794, 11556849, 12172394). ClinVar contains an entry for this variant (Variation ID: 167134). Experimental studies have shown that this missense change does not disrupt GJB2 channel localization or channel currents but it does disrupt the intercellular transport of a second messenger and some large molecules (PMID: 12505163, 12562518, 15592461, 20441744, 16217030). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000169112 SCV001437384 pathogenic Deafness, autosomal recessive 1A 2020-09-03 criteria provided, single submitter clinical testing Variant summary: GJB2 c.250G>T (p.Val84Leu) results in a conservative amino acid change located in the Connexin, N-terminal domain (IPR013092) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251338 control chromosomes (gnomAD). c.250G>T has been reported in the literature, in the compound heterozygous and homozygous state, in multiple individuals affected with Autosomal Recessive Non-Syndromic Hearing Loss (e.g. Kenna_2001, Wu_2002, Snoeckx_2005, Putcha_2007, Minami_2013, Carranza_2016). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant retains electrophysiological properties but affects the intercellular exchange of large molecules (such as IP3 transfer) (e.g. Bruzzone_2003, Wang_2003, Beltramello_2005, Zhang_2005, Ambrosi_2010). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Counsyl RCV000169112 SCV000220314 pathogenic Deafness, autosomal recessive 1A 2017-11-13 no assertion criteria provided clinical testing

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