ClinVar Miner

Submissions for variant NM_000166.6(GJB1):c.541G>A (p.Val181Met) (rs879253909)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235289 SCV000292763 pathogenic not provided 2020-10-05 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 9361298, 17100997, 31372974, 19259128, 21692908, 25947624, 28071741, 32903794, 33136338)
Athena Diagnostics Inc RCV000235289 SCV000841720 pathogenic not provided 2016-07-01 criteria provided, single submitter clinical testing
Invitae RCV000804182 SCV000944078 pathogenic Charcot-Marie-Tooth Neuropathy X 2020-05-21 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 181 of the GJB1 protein (p.Val181Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with Charcot-Marie-Tooth disease (PMID: 9361298, 17100997, 19259128, 21692908, 25947624). ClinVar contains an entry for this variant (Variation ID: 245705). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C1). Variants that disrupt the p.Val181 amino acid residue in GJB1 have been observed in affected individuals (PMID: 14627639, 18380028). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Inherited Neuropathy Consortium RCV000789192 SCV000928544 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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