ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.1070C>G (p.Ala357Gly) (rs863223437)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000199512 SCV000249730 uncertain significance not provided 2017-05-03 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CBS gene. The A357G variant has been reported to be benign based on an in vivo yeast assay designed to determine the effect of single amino acid substitutions on CBS enzyme activity. A357G was presumed benign as it did not impact yeast growth rates compared to wild-type (Dimster-Denk et al., 2013). The A357G variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Nevertheless, this variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function.
Invitae RCV000473415 SCV000543515 uncertain significance Homocystinuria due to CBS deficiency 2018-07-30 criteria provided, single submitter clinical testing This sequence change replaces alanine with glycine at codon 357 of the CBS protein (p.Ala357Gly). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and glycine. 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: 212880). 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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