ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.670C>T (p.Arg224Cys) (rs139456571)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000726462 SCV000249689 uncertain significance not provided 2018-09-11 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CBS gene. The R244C variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 26/66,634 (0.04%) alleles from individuals of European ancestry from the Exome Aggreagtion Consortium (ExAC) data set (Lek et al., 2016). Nevertheless, the R224C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position that is conserved across species. Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function.
Ambry Genetics RCV000243693 SCV000318560 uncertain significance Cardiovascular phenotype 2013-04-17 criteria provided, single submitter clinical testing Insufficient or inconclusive evidence
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000726462 SCV000344856 uncertain significance not provided 2016-08-15 criteria provided, single submitter clinical testing
Invitae RCV000556147 SCV000649845 uncertain significance Classic homocystinuria 2019-07-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 224 of the CBS protein (p.Arg224Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs139456571, ExAC 0.04%). This variant has not been reported in the literature in individuals with CBS-related disease. ClinVar contains an entry for this variant (Variation ID: 212851). 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: "Deleterious"; PolyPhen-2: "Benign"; 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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