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 2015-03-24 criteria provided, single submitter clinical testing The V181M missense mutation in the GJB1 gene has been reported previously in association with CMTX1 (Bone et al., 1997; Casasnovas et al., 2006; Miltenberger-Miltenyi et al., 2009; European CMT Consortium Mutation Database). Additionally, different amino acid substitutions at this same position (V181L, V181A) and in the adjacent residues (F180L, F180S, S182C, S182T) have been reported in association with CMTX1 (Stenson et at., 2014), supporting the functional significance of this region of the protein. V181M was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved through mammals. Therefore, the presence of the V181M mutation is consistent with a diagnosis of CMTX1
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 2019-10-07 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 C15"). 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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