Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002232228 | SCV000769924 | pathogenic | HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED | 2023-07-08 | criteria provided, single submitter | clinical testing | This variant is present in population databases (rs779270933, gnomAD 0.007%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 302 of the CBS protein (p.Glu302Lys). This missense change has been observed in individuals with homocystinuria (PMID: 10338090, 12124992, 29326875; Invitae). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CBS function (PMID: 10338090, 20506325, 22267502). 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. ClinVar contains an entry for this variant (Variation ID: 496864). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001805199 | SCV002051128 | likely pathogenic | Homocystinuria | 2021-12-15 | criteria provided, single submitter | clinical testing | Variant summary: CBS c.904G>A (p.Glu302Lys) results in a conservative amino acid change located in the Pyridoxal-phosphate dependent enzyme domain (IPR001926) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251416 control chromosomes. c.904G>A has been reported in the literature as a compound heterozygous genotype in individuals affected with Homocystinuria (example, Kraus_1999, Gaustadnes_2002, Voskoboeva_2018). These data indicate that the variant may be associated with disease. Several publications report experimental evidence evaluating an impact on protein function (example, deFranchis_1999, Kozich_2010, Mayfield_2012). The most pronounced variant effect results in 4.9% of normal CBS enzyme activity when expressed in Ecoli extracts and a shorter than expected subunit size by western blot analysis suggestive of partial degradation of the mutant enzyme (deFranchis_1999), inhibited by AdoHcy and not activated by AdoMet (Kozich_2010), and a nonfunctional outcome in yeast as measured by ortholog replacement in Saccharomyces cerevisiae (Mayfield_2012). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic and one laboratory classified the variant as uncertain significance. One submitter cites overlapping evidence utilized in the context of this evalution. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Baylor Genetics | RCV003459461 | SCV004215556 | pathogenic | Classic homocystinuria | 2022-11-28 | criteria provided, single submitter | clinical testing | |
| Eurofins Ntd Llc |
RCV000723460 | SCV000700449 | uncertain significance | not provided | 2017-04-12 | flagged submission | clinical testing |