ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.1072G>A (p.Val358Met) (rs148589243)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000420634 SCV000225480 uncertain significance not provided 2015-02-23 criteria provided, single submitter clinical testing
GeneDx RCV000199585 SCV000249707 uncertain significance not specified 2017-07-03 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CBS gene. The V358M variant has not been published as pathogenic or been reported as benign to our knowledge. Additionally, this variant has been observed in 11/62066 (0.02%) alleles from individuals of Non-Finnish European ancestry in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Although this substitution occurs at a position that is largely conserved across species, methionine (M) is the wild-type residue at this position in at least one mammalian species. Furthermore, V358M is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Nevertheless, in silico analysis predicts this variant is probably damaging to the protein structure/function.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000420634 SCV000510675 uncertain significance not provided 2016-07-06 criteria provided, single submitter clinical testing Converted during submission to Uncertain significance.
Invitae RCV000474043 SCV000543512 uncertain significance Classic homocystinuria 2019-12-03 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 358 of the CBS protein (p.Val358Met). The valine residue is moderately conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs148589243, ExAC 0.02%). This variant has not been reported in the literature in individuals with a CBS-related disease. ClinVar contains an entry for this variant (Variation ID: 193971). 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, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function or cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Clinical Services Laboratory,Illumina RCV000474043 SCV001300404 uncertain significance Classic homocystinuria 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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