ClinVar Miner

Submissions for variant NM_000166.6(GJB1):c.490C>T (p.Arg164Trp) (rs139643362)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000201175 SCV000255690 pathogenic Charcot-Marie-Tooth Neuropathy X Type 1 2013-02-15 criteria provided, single submitter clinical testing
GeneDx RCV000307118 SCV000329810 pathogenic not provided 2016-07-29 criteria provided, single submitter clinical testing The R164W pathogenic variant has been published numerous times in association with CMT (Ionasescu et al., 1995; Ionasescu et al., 1996; Oterino et al., 1996; Young et al., 2001). Functional studies using dual whole-cell voltage-clamp recordings show that R164W impaired the formation and function of junctional channels (Wang et al., 2004). Additionally, different amino acid substitutions at this same position (R164G/Q) and in nearby residues have been reported in the Human Gene Mutation Database in association with CMT (Stenson et al., 2014), supporting the functional significance of this region of the protein. R164W was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. R164W is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. Therefore, R164W is interpreted to be a pathogenic variant.
Invitae RCV000793229 SCV000932572 pathogenic Charcot-Marie-Tooth Neuropathy X 2019-07-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 164 of the GJB1 protein (p.Arg164Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed to segregate with Charcot-Marie-Tooth disease (CMT) in a family (PMID: 8733054) and has been reported in many unrelated individuals with CMT (PMID: 7580242, 8733054, 11437164, 28469099). This variant is also known as c.552C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 217170). Experimental studies have shown that this missense change results in mislocalization of the GJB1 protein as well as reduced protein function in a mammalian cell expression assay (PMID: 11571214, 15006706). This variant disrupts the p.Arg164 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 9187667, 25025039, 27844031), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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