ClinVar Miner

Submissions for variant NM_000166.5(GJB1):c.547C>T (p.Arg183Cys) (rs863224471)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000235360 SCV000613490 likely pathogenic not provided 2017-12-29 criteria provided, single submitter clinical testing
GeneDx RCV000235360 SCV000293450 pathogenic not provided 2018-12-04 criteria provided, single submitter clinical testing The R183C pathogenic variant in the GJB1 gene has been previously reported in association with CMTX in affected males and females (Bone et al., 1997, Hahn et al., 2001, Bort et al., 1997). 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 R183C 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 across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Multiple missense variants at the same codon (R183H/S/P) and in nearby residues have been reported in the Human Gene Mutation Database in association with GJB1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, the presence of the R183C pathogenic variant is consistent with the diagnosis of CMTX
Inherited Neuropathy Consortium RCV000789836 SCV000929220 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only
Invitae RCV000197033 SCV000253768 pathogenic Charcot-Marie-Tooth Neuropathy X 2018-04-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 183 of the GJB1 protein (p.Arg183Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with Charcot-Marie-Tooth disease (PMID: 28469099, 25429913, 9187667, 11271367). ClinVar contains an entry for this variant (Variation ID: 216039). Experimental studies have shown that this missense change causes the GJB1 protein to concentrate in the Golgi apparatus instead of migrating to the cell membrane for proper function (PMID: 1211842, 27844031). A different missense substitution at this codon (p.Arg183His) has been determined to be pathogenic (PMID: 9187667, 27844031, 15719046, 27027447). This suggests that the arginine residue is critical for GJB1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
NeuroMeGen,Hospital Clinico Santiago de Compostela RCV000754745 SCV000882635 likely pathogenic X-linked hereditary motor and sensory neuropathy 2018-10-08 criteria provided, single submitter clinical testing

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