ClinVar Miner

Submissions for variant NM_000166.6(GJB1):c.223C>T (p.Arg75Trp) (rs116840819)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236563 SCV000293446 pathogenic not provided 2016-05-10 criteria provided, single submitter clinical testing The R75W pathogenic variant has been previously reported in association with CMTX1 (Silander et al., 1997; Latour et al., 1997; Casasnovas et al., 2006, GJB1 LOVD database). The Arg75 residue is highly conserved across connexin proteins and published functional studies demonstrate a damaging effect on the gene product (Yum et al., 2002; Abrams et al., 2013). 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. R75W is a non-conservative amino acid substitution. Additionally, different amino acid substitutions at this position (R75P, R75Q) 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, the presence of the R75W pathogenic variant is consistent with a diagnosis of CMTX
Invitae RCV000654844 SCV000776746 pathogenic Charcot-Marie-Tooth Neuropathy X 2020-07-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 75 of the GJB1 protein (p.Arg75Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple individuals and families affected with Charcot-Marie-Tooth disease (CMT) (PMID: 9272161, 14663027, 12402337, 10732813, 15719046, 17100997). ClinVar contains an entry for this variant (Variation ID: 21082). Experimental studies have shown that this missense change prevents the formation of functional GJB1 gap junctions and leads to a CMT-like phenotype in transgenic mice (PMID: 19369543, 12460545, 23209285). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000020172 SCV001158504 pathogenic Charcot-Marie-Tooth Neuropathy X Type 1 2019-06-11 criteria provided, single submitter clinical testing The GJB1 c.223C>T; p.Arg75Trp variant (rs116840819) is reported frequently in the literature in individuals affected with X-linked Charcot-Marie-Tooth neuropathy (select references: Silander 1997, Zhang 2005, Parissis 2017, and Bacquet 2018). Functional analyses of the variant protein in cell culture and transgenic mice show that the p.Arg75Trp variant causes defects in GJB1 protein function consistent with known CMT disease mechanisms (Sargiannidou 2009, Abrams 2013). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Based on available information, this variant is considered to be pathogenic.
Athena Diagnostics Inc RCV000236563 SCV001880849 pathogenic not provided 2021-01-08 criteria provided, single submitter clinical testing This variant has not been reported in large, multi-ethnic general populations ( This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies showed defective protein activity and transgenic mice with a demyelinating neuropathy (PMID: 12460545, 19369543, 23209285, 28334782). Computational tools predict that this variant is damaging.
GeneReviews RCV000020172 SCV000040501 pathologic Charcot-Marie-Tooth Neuropathy X Type 1 2010-04-15 no assertion criteria provided curation Converted during submission to Pathogenic.
Inherited Neuropathy Consortium RCV000789309 SCV000928662 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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