ClinVar Miner

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

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Total submissions: 4
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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 2017-12-27 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.
GeneReviews RCV000020172 SCV000040501 pathologic X-linked hereditary motor and sensory neuropathy 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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