ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.65A>G (p.His22Arg) (rs763151207)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000197426 SCV000249717 uncertain significance not provided 2018-05-31 criteria provided, single submitter clinical testing The H22R variant in the CBS gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The H22R variant was not observed in approximately 6,500 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 H22R 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 not conserved. In silico analysis predicts this variant likely does not alter the protein structure/function. We interpret H22R as a variant of uncertain significance.
Invitae RCV000648122 SCV000769935 uncertain significance Homocystinuria due to CBS deficiency 2017-12-29 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 22 of the CBS protein (p.His22Arg). The histidine residue is weakly conserved and there is a small physicochemical difference between histidine and arginine. This variant is present in population databases (rs763151207, ExAC 0.008%). This variant has not been reported in the literature in individuals with CBS-related disease. ClinVar contains an entry for this variant (Variation ID: 212870). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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