Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002242773 | SCV001575604 | pathogenic | HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED | 2024-10-18 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 290 of the CBS protein (p.Pro290Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with homocystinuria (PMID: 7564249, 8803779). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1066972). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CBS protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CBS function (PMID: 22267502). For these reasons, this variant has been classified as Pathogenic. |
| Ce |
RCV003883622 | SCV004699822 | likely pathogenic | not provided | 2024-02-01 | criteria provided, single submitter | clinical testing | CBS: PM2, PM3, PP4:Moderate, PS3:Supporting |
| Baylor Genetics | RCV004570927 | SCV005060015 | likely pathogenic | Classic homocystinuria | 2024-03-20 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV005237766 | SCV005886770 | likely pathogenic | Homocystinuria | 2025-02-03 | criteria provided, single submitter | clinical testing | Variant summary: CBS c.869C>T (p.Pro290Leu) results in a non-conservative amino acid change located in the Pyridoxal-phosphate dependent enzyme domain (IPR001926) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 241568 control chromosomes. c.869C>T has been reported in the simple heterozygous state or compound heterozygous state in the literature in individuals affected with clinical features of Homocystinuria (example, DeFranchis_1998, Karaca_2014, Sperandeo_1995, Sperandeo_1996), including at least 1 individual who carried a pathogenic variant in trans. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in poor growth in an in vitro yeast model with or without high B6 supplementation (example, Mayfield, 2012). The following publications have been ascertained in the context of this evaluation (PMID: 9587029, 24211323, 22267502, 7564249, 8803779). ClinVar contains an entry for this variant (Variation ID: 1066972). Based on the evidence outlined above, the variant was classified as likely pathogenic. |