ClinVar Miner

Submissions for variant NM_000166.6(GJB1):c.239A>G (p.Gln80Arg) (rs879254097)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235814 SCV000293448 likely pathogenic not provided 2018-02-14 criteria provided, single submitter clinical testing The Q80R variant has been previously reported previously in association with CMTX1 (Ionasescu et al., 1995; Mersiyanova et al., 2000). Functional studies show that the Q80R variant is capable of forming a functional gap junction protein, and the authors conclude that further functional studies are necessary to elucidate the effect, if any, of the Q80R variant (Wang et al., 2004). 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 Q80R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, a different amino acid substitution at this same position (Q80K) and missense variants in nearby residues 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 likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV000466555 SCV000544779 likely pathogenic Charcot-Marie-Tooth Neuropathy X 2016-07-18 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 80 of the GJB1 protein (p.Gln80Arg). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in 5 individuals affected with X-linked Charcot-Marie-Tooth (CMT) disease (PMID: 7580242, 8737658, 17353473, 10737979. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this is a rare missense change that has been reported in several affected individuals, and is predicted to disrupt protein function. Functional studies demonstrating a mechanism for pathogenicity have not been published. For these reasons, this variant has been classified as likely Pathogenic.
Athena Diagnostics Inc RCV000235814 SCV000613480 pathogenic not provided 2016-12-22 criteria provided, single submitter clinical testing
Inherited Neuropathy Consortium RCV000789226 SCV000928578 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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