ClinVar Miner

Submissions for variant NM_000071.3(CBS):c.262C>G (p.Pro88Ala)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV002601595 SCV002949845 likely pathogenic HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED 2022-09-13 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 88 of the CBS protein (p.Pro88Ala). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Pro88 amino acid residue in CBS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7762555, 22267502). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CBS protein function. This variant has not been reported in the literature in individuals affected with CBS-related conditions. This variant is not present in population databases (gnomAD no frequency).
Neuberg Centre For Genomic Medicine, NCGM RCV003340518 SCV004047692 uncertain significance Classic homocystinuria criteria provided, single submitter clinical testing The missense variant c.262C>G (p.Pro88Ala) in CBS gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Pro88Ala variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid Pro at position 88 is changed to a Ala changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Pro88Ala in CBS is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS).

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