Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV003154014 | SCV001557199 | likely pathogenic | HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED | 2023-09-21 | criteria provided, single submitter | clinical testing | 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. 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.Arg336 amino acid residue in CBS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10408774, 12815602, 16205833, 16429402, 21517828, 26464485). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 1052953). 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). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 336 of the CBS protein (p.Arg336Pro). |
| Ambry Genetics | RCV002420789 | SCV002725410 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2022-08-04 | criteria provided, single submitter | clinical testing | The p.R336P variant (also known as c.1007G>C), located in coding exon 9 of the CBS gene, results from a G to C substitution at nucleotide position 1007. The arginine at codon 336 is replaced by proline, an amino acid with dissimilar properties. This alteration has been reported as compound heterozygous with a known pathogenic mutation in CBS in an individual with homocystinuria (Ambry internal data). Another alteration at the same codon, p.R336H (c.1007G>A), has been detected as homozygous in two family members with homocystinuria (Coudé M et al. J Inherit Metab Dis, 1998 Dec;21:823-8), and showed an impact on enzyme activity in functional studies (Urreizti R et al. Hum Mutat, 2006 Feb;27:211; Mayfield JA et al. Genetics, 2012 Apr;190:1309-23; Mendes MI et al. Hum Mol Genet, 2015 Dec;24:7339-48). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Natera, |
RCV001361230 | SCV002083782 | uncertain significance | Classic homocystinuria | 2020-04-24 | no assertion criteria provided | clinical testing |