Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002311162 | SCV000320330 | uncertain significance | Familial thoracic aortic aneurysm and aortic dissection | 2023-04-11 | criteria provided, single submitter | clinical testing | The p.G453E variant (also known as c.1358G>A), located in coding exon 12 of the CBS gene, results from a G to A substitution at nucleotide position 1358. The amino acid change results in glycine to glutamic acid at codon 453, an amino acid with similar properties. This alteration is located in the regulatory domain of CBS protein. However, this change occurs in the last base pair of coding exon 12, which makes it likely to have some effect on normal mRNA splicing. In an in vitro study in yeast, the p.G453E showed comparable enzyme activity to the wild type. In addition, when expressed in cis with a pathogenic mutation, this variant was shown to rescue the yeast phenotype and restore the enzyme activity to a limited extent (Shan X et al, Hum. Mol. Genet. 2001 Mar; 10(6):635-43). However, the potential impact this variant has on splicing was not addressed in that study. This nucleotide position is highly conserved in available vertebrate species. This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. In addition, as a missense substitution this 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. |
| Mendelics | RCV000990350 | SCV001141296 | uncertain significance | Classic homocystinuria | 2019-05-28 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV002518722 | SCV003011997 | uncertain significance | HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED | 2022-01-17 | criteria provided, single submitter | clinical testing | 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change affects CBS function (PMID: 11230183). 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 264408). 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 glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 453 of the CBS protein (p.Gly453Glu). This variant also falls at the last nucleotide of exon 14, which is part of the consensus splice site for this exon. |
| Revvity Omics, |
RCV000990350 | SCV003829290 | uncertain significance | Classic homocystinuria | 2021-08-05 | criteria provided, single submitter | clinical testing | |
| Natera, |
RCV000990350 | SCV002083766 | uncertain significance | Classic homocystinuria | 2020-02-10 | no assertion criteria provided | clinical testing |