Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000675119 | SCV000800673 | uncertain significance | Classic homocystinuria | 2018-03-12 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000000153 | SCV002128242 | uncertain significance | HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED | 2022-05-09 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 466 of the CBS protein (p.Ser466Leu). This variant is present in population databases (rs121964971, gnomAD 0.003%). This missense change has been observed in individual(s) with homocystinuria due to cystathionine beta-synthase (CBS) deficiency (PMID: 10338090). ClinVar contains an entry for this variant (Variation ID: 130). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects CBS function (PMID: 22612060, 23592311). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Ambry Genetics | RCV002390082 | SCV002702257 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2022-09-16 | criteria provided, single submitter | clinical testing | The p.S466L variant (also known as c.1397C>T), located in coding exon 13 of the CBS gene, results from a C to T substitution at nucleotide position 1397. The serine at codon 466 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported as a heterozygote and compound heterozygote in subjects with vascualar or thrombotic presentations (Kraus JP et al. Hum Mutat, 1999;13:362-75; Maclean KN et al. Hum Mutat, 2002 Jun;19:641-55). Functional studies suggest a possible impact on function; but the clinical significance of these studies is unclear (Gupta S et al. Hum Mutat, 2008 Aug;29:1048-54; Mayfield JA et al. Genetics, 2012 Apr;190:1309-23; Pey AL et al. Biochem J, 2013 Jan;449:109-21). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Fulgent Genetics, |
RCV000675119 | SCV002782907 | uncertain significance | Classic homocystinuria | 2021-10-25 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003226154 | SCV003922491 | uncertain significance | not specified | 2023-03-10 | criteria provided, single submitter | clinical testing | Variant summary: CBS c.1397C>T (p.Ser466Leu) results in a non-conservative amino acid change located in the CBS domain (IPR000644) 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 1.2e-05 in 251394 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1397C>T has been reported in the literature in at least one individual suffering premature thrombosis but lacking any of the connective tissue disorders typical of homocystinuria due to CBS deficiency (Kraus_1999, Maclean_2002). These data do not allow any conclusion about variant significance. Experimental evidence demonstrated the variant to be catalytically active but deficient in its response to S-adenosylmethionine (AdoMet), and indicated that it affects the steady state level of CBS protein and reduces the efficiency of the enzyme in vivo (Maclean_2002, Gupta_2008, Kozich_2010, Melenovska_2015). However, these findings do not allow unequivocal conclusions about the clinical significance of the variant. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Baylor Genetics | RCV000675119 | SCV004213886 | likely pathogenic | Classic homocystinuria | 2023-08-10 | criteria provided, single submitter | clinical testing | |
| OMIM | RCV000000153 | SCV000020296 | pathogenic | HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED | 2008-08-01 | no assertion criteria provided | literature only |