ClinVar Miner

Submissions for variant NM_000166.6(GJB1):c.548G>A (p.Arg183His) (rs1555937233)

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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 RCV000517827 SCV000613491 pathogenic not provided 2021-03-10 criteria provided, single submitter clinical testing This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with X-linked Charcot-Marie-Tooth neuropathy, type 1 (CMTX1). At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant causes aberrant cellular localization of this gap junction protein (PMID: 12111842). This variant alters a critical location within the protein, and is expected to severely affect function and cause disease. Computational tools predict that this variant is damaging.
Invitae RCV000654852 SCV000776754 pathogenic Charcot-Marie-Tooth Neuropathy X 2019-06-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 183 of the GJB1 protein (p.Arg183His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals and families affected with Charcot-Marie-Tooth disease, type X (PMID: 9187667, 27844031, 15719046, 27027447, 14960772, 28469099). Experimental studies have shown that this affects protein expression and function (PMID: 27844031, 12111842). A different missense substitution at this codon (p.Arg183Cys) has been determined to be pathogenic (PMID: 9187667, 11271367, 12111842). 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000517827 SCV001245766 pathogenic not provided 2016-11-01 criteria provided, single submitter clinical testing
Inherited Neuropathy Consortium RCV000789837 SCV000929221 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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