ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.616G>A (p.Val206Met) (rs369220569)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000200147 SCV000249687 uncertain significance not provided 2016-03-07 criteria provided, single submitter clinical testing The V206M variant of uncertain significance in the CBS gene has not been published as a pathogenic variant or been reported as a benign variant to our knowledge. The V206M variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. Although the V206M variant occurs at a position that is conserved across species, it is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, no missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with homocystinuria. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000648123 SCV000769937 uncertain significance Homocystinuria due to CBS deficiency 2018-01-04 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 206 of the CBS protein (p.Val206Met). The valine residue is moderately conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs369220569, ExAC 0.003%). This variant has not been reported in the literature in individuals with CBS-related disease. ClinVar contains an entry for this variant (Variation ID: 212849). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly 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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