ClinVar Miner

Submissions for variant NM_000166.6(GJB1):c.643C>T (p.Arg215Trp)

dbSNP: rs879254099
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236009 SCV000293451 pathogenic not provided 2024-03-26 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect as R215W prevents the formation of functional channels (PMID: 8816997, 10234007); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10234007, 11835375, 8162049, 11571214, 32376792, 34326750, 8816997)
Athena Diagnostics RCV000236009 SCV000613497 pathogenic not provided 2016-11-18 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000688999 SCV000816633 pathogenic Charcot-Marie-Tooth Neuropathy X 2023-11-19 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 215 of the GJB1 protein (p.Arg215Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Charcot-Marie-Tooth disease, type 1X (CMT1X) (PMID: 8162049, 8698335, 9187667, 11437164, 11571214, 11835375, 16912585, 22464564, 25947624, 27098783). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 246098). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GJB1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GJB1 function (PMID: 8816997, 10234007). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center RCV003388834 SCV004100753 likely pathogenic Charcot-Marie-Tooth disease X-linked dominant 1 2023-09-25 criteria provided, single submitter clinical testing Criteria applied: PS4_MOD,PM5,PS3_SUP,PM2_SUP,PP3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003388834 SCV004223162 pathogenic Charcot-Marie-Tooth disease X-linked dominant 1 2023-11-27 criteria provided, single submitter clinical testing Variant summary: GJB1 c.643C>T (p.Arg215Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 179956 control chromosomes. c.643C>T has been reported in the literature in multiple familial individuals affected with Charcot-Marie-Tooth disease X-linked dominant 1 (example, Fairweather_1994, Kovale_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in about 20% of normal GJB1 levels, diminished gap junctional intercellular communication, and interfering WT allele of GJB1 through a dominant-negative mechanism in Hela cells (Omori_1996). The following publications have been ascertained in the context of this evaluation (PMID: 8162049, 34326750, 8816997). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Inherited Neuropathy Consortium RCV000789850 SCV000929235 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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