Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002468954 | SCV002766587 | uncertain significance | not specified | 2022-11-06 | criteria provided, single submitter | clinical testing | Variant summary: CBS c.415G>A (p.Gly139Arg) results in a non-conservative amino acid change located in the Tryptophan synthase beta chain-like, PALP 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 allele was found at a frequency of 2.8e-05 in 250444 control chromosomes (gnomAD). c.415G>A has been reported in the literature in at least one compound heterozygous individual affected with Homocystinuria (Shih_1995). These data do not allow any conclusion about variant significance. One publication using a yeast ortholog replacement assay reports experimental evidence indicating the variant has an intermediate phenotype that is responsive to B6 supplementation (Mayfield_2012). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
| Invitae | RCV003764500 | SCV004649013 | likely pathogenic | HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED | 2023-12-17 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 139 of the CBS protein (p.Gly139Arg). This variant is present in population databases (rs121964965, gnomAD 0.01%). This missense change has been observed in individual(s) with homocystinuria due to CBS deficiency (PMID: 7611293). ClinVar contains an entry for this variant (Variation ID: 121). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CBS function (PMID: 22267502). 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. |
| OMIM | RCV000000143 | SCV000020286 | pathogenic | Homocystinuria, pyridoxine-responsive | 1995-07-01 | no assertion criteria provided | literature only |