ClinVar Miner

Submissions for variant NM_000166.6(GJB1):c.8G>C (p.Trp3Ser) (rs1555936989)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000654850 SCV000776752 uncertain significance Charcot-Marie-Tooth Neuropathy X 2017-11-16 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with serine at codon 3 of the GJB1 protein (p.Trp3Ser). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Charcot-Marie-Tooth disease (PMID: 8737658). Experimental studies have shown that this missense change impairs gap junction activity of the GJB1 protein product in a cell-cell dye transfer assay (PMID: 10646523). Two different missense substitutions at this codon, p.Trp3Arg and p.Trp3Gly, have been reported in individuals with Charcot-Marie-Tooth disease; the latter variant (p.Trp3Gly) was reported as a de novo mutation in the affected individual (PMID: 8737658, 21922480). A third missense substitution, p.Trp3Tyr, has been reported to impair protein function as assayed by a cell-cell dye transfer assay (PMID: 10646523). This suggests that the tryptophan residue is critical for GJB1 protein function, however, additional data are needed to prove this conclusively. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Molecular Genetics Laboratory,London Health Sciences Centre RCV000789228 SCV001336649 pathogenic Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing
Inherited Neuropathy Consortium RCV000789228 SCV000928580 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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