ClinVar Miner

Submissions for variant NM_000166.5(GJB1):c.467T>G (p.Leu156Arg) (rs104894818)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000256065 SCV000841717 pathogenic not provided 2017-12-29 criteria provided, single submitter clinical testing
GeneDx RCV000256065 SCV000322234 pathogenic not provided 2017-02-23 criteria provided, single submitter clinical testing The L156R variant in the GJB1 gene has been previously published in families with X-linked Charcot-Marie-Tooth disease (Bergoffen et at., 1993; Bone et al., 1995). 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 L156R 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. It occurs within the extracellular domain located between the third and fourth transmembrane domains of the protein. Although this substitution occurs at a position where amino acids with similar properties to Leucine are tolerated across species, in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants at the same residue (L156F) and in nearby residues (Y151H/N/S, V152D, F153C/S, Y157C, P158A/S/R, G159S/D, Y160H/C, A161P/D) have been reported in the Human Gene Mutation Database in association with Charcot-Marie-Tooth disease (Stenson et al., 2014), supporting the functional importance of this region of the protein. In addition, the GJB1 gene has a low rate of benign missense variation with missense variants being a common mechanism of disease.
Invitae RCV000463876 SCV000544773 likely pathogenic Charcot-Marie-Tooth Neuropathy X 2018-06-02 criteria provided, single submitter clinical testing This sequence change replaces leucine with arginine at codon 156 of the GJB1 protein (p.Leu156Arg). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple individuals affected with Charcot-Marie-Tooth disease (PMID: 7477983, 8266101, 9018031, 17353473, 26955336). ClinVar contains an entry for this variant (Variation ID: 10437). Experimental studies have shown that this missense change adversely affects protein function (PMID: 15006706). In summary, this variant is a rare missense change that has been reported in affected individuals and has been shown to affect protein function. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
OMIM RCV000011182 SCV000031409 pathogenic X-linked hereditary motor and sensory neuropathy 1995-10-01 no assertion criteria provided literature only

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