ClinVar Miner

Submissions for variant NM_000166.6(GJB1):c.65G>A (p.Arg22Gln) (rs1060501002)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000475257 SCV000544775 pathogenic Charcot-Marie-Tooth Neuropathy X 2018-11-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 22 of the GJB1 protein (p.Arg22Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been shown to segregate with Charcot-Marie-Tooth disease (CMT) in several families (PMID: 10521546, 8737658, 7580242, 9633821, 11835375, 9272161) and has also been reported in several individuals affected with CMT (PMID: 12542510, 17353473, 9600589, 26454100). In one of these individuals, this variant was shown to arise de novo (PMID: 9272161). ClinVar contains an entry for this variant (Variation ID: 406228). Experimental studies performed in different cell lines report conflicting results, with one study reporting that the p.Arg22Gln mutant is retained in the Golgi apparatus and another study reporting that the mutant protein is able to localize correctly and form functional channels (PMID: 15006706, 11393532). Due to strong genetic evidence, this variant has been classified as Pathogenic.
Athena Diagnostics Inc RCV000517974 SCV000613500 pathogenic not provided 2016-03-09 criteria provided, single submitter clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000853377 SCV000996248 likely pathogenic X-linked hereditary motor and sensory neuropathy 2019-02-20 criteria provided, single submitter clinical testing This variant has been previously reported as heterozygous or hemizygous change in patients with Charcot-Marie-Tooth disease (PMID: 7580242, 12542510). The variant has been reported as pathogenic by two clinical laboratories in the ClinVar database (SCV000544775, SCV000613500). In vitro studies on the functional impact of the p.Arg22Gln variant are conflicting (PMID: 11393532, 15006706). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.65G>A (p.Arg22Gln) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.65G>A (p.Arg22Gln) variant is classified as likely pathogenic.
Inherited Neuropathy Consortium RCV000789225 SCV000928577 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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