ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.1472G>A (p.Arg491His) (rs747419767)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000249170 SCV000317330 uncertain significance Cardiovascular phenotype 2013-06-17 criteria provided, single submitter clinical testing
GeneDx RCV000483442 SCV000573855 uncertain significance not provided 2017-03-08 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CBS gene. The R491H variant has not been published as pathogenic or been reported as benign to our knowledge. Additionally, this variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). However, the R491H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, this substitution occurs at a position that is not conserved across species and histidine (H) is the wild-type residue at this position in multiple species. In silico analysis predicts this variant likely does not alter the protein structure/function. Furthermore, although a missense variant at the same residue in the CBS gene (R491C) has been previously reported in association with homocystinuria (Kraus et al., 1999), the clinical significance of this variant also remains to be definitively determined. Finally, R491H is classified as a variant of uncertain significance in ClinVar by another clinical laboratory (ClinVar SCV000317330.1; Landrum et al., 2016).

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