ClinVar Miner

Submissions for variant NM_014000.2(VCL):c.1298G>A (p.Arg433His) (rs754046223)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183997 SCV000236491 uncertain significance not provided 2018-09-13 criteria provided, single submitter clinical testing p.Arg433His (CGT>CAT): c.1298 G>A in exon 10 of the VCL gene (NM_014000.2)A variant of unknown significance has been identified in the VCL gene. The R433H variant has not been published as a mutation or a benign polymorphism to our knowledge. The R433H variant 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. The R433H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. No missense mutations in nearby residues have been reported in association with cardiomyopathy.Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s).
Invitae RCV000804406 SCV000944315 uncertain significance Dilated cardiomyopathy 1W 2018-10-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 433 of the VCL protein (p.Arg433His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs754046223, ExAC 0.006%). This variant has not been reported in the literature in individuals with VCL-related disease. ClinVar contains an entry for this variant (Variation ID: 202158). 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 C0"). 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.

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