ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.750G>A (p.Met250Ile) (rs863223431)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000198250 SCV000249692 uncertain significance not provided 2014-05-10 criteria provided, single submitter clinical testing p.Met250Ile (ATG>ATA): c.750 G>A in exon 9 of the CBS gene (NM_000071.2). A variant of unknown significance has been identified in the CBS gene. The M250I variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The M250I variant was not observed in approximately 6500 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 M250I 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. Missense mutations in nearby residues (L251P, T257M, G259S) have been reported in association with Homocystinuria, supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. This variant was found in TAAD
Invitae RCV000800742 SCV000940473 uncertain significance Homocystinuria due to CBS deficiency 2018-11-20 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 250 of the CBS protein (p.Met250Ile). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CBS-related disease. ClinVar contains an entry for this variant (Variation ID: 212854). 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: "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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