ClinVar Miner

Submissions for variant NM_000166.6(GJB1):c.376C>T (p.His126Tyr) (rs879253995)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236069 SCV000293099 likely pathogenic not provided 2015-09-02 criteria provided, single submitter clinical testing The H126Y variant has been previously reported in a male patient with features of CMT; the variant was also identified in his mother and sister who had pes cavus, his maternal uncle with foot deformities and walking difficulty, and in a younger brother and sister who were both clinically unaffected at 10 and 8 years of age, respectively (Verhelst et al., 2000). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The H126Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense variants in nearby residues (V120E, K124N, V125D, I127F/S/M, S128P/L, T130I, L131P) have been reported in the Human Gene Mutation Database in association with CMTX1 (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded.
Invitae RCV000698707 SCV000827387 likely pathogenic Charcot-Marie-Tooth Neuropathy X 2018-04-25 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 126 of the GJB1 protein (p.His126Tyr). The histidine residue is moderately conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with X-linked Charcot-Marie-Tooth (CMTX) disease in a family (PMID: 11030070) and has been reported in several individuals affected with CMTX (PMID: 28768847). ClinVar contains an entry for this variant (Variation ID: 245904). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Inherited Neuropathy Consortium RCV000789056 SCV000928405 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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