ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.502G>A (p.Val168Met) (rs121964970)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000179250 SCV000231470 uncertain significance not provided 2017-08-29 criteria provided, single submitter clinical testing
GeneDx RCV000179250 SCV000249683 likely pathogenic not provided 2021-05-19 criteria provided, single submitter clinical testing Has been reported in individuals with B6-responsive homocystinuria (Kruger et al., 1995; Shan et al., 1998), as well as an individual with spontaneous coronary artery dissection (SCAD) (Kaadan et al., 2018).; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies in yeast have demonstrated that V168M results in a non-functional allele with impaired CBS function (Shan et al., 1998; Mayfield et al., 2012).; Reported in ClinVar (ClinVar Variant ID# 127; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 10338090, 10531322, 31301157, 8528202, 22267502, 29650765, 9590298, 11230183, 20066033)
Ambry Genetics RCV000250042 SCV000317362 uncertain significance Cardiovascular phenotype 2019-08-22 criteria provided, single submitter clinical testing The p.V168M pathogenic mutation (also known as c.502G>A), located in coding exon 4 of the CBS gene, results from a G to A substitution at nucleotide position 502. The valine at codon 168 is replaced by methionine, an amino acid with highly similar properties. This variant was first reported as detected in cell lines from an individual with inferred clinical phenotype of homozygous CBS enzyme deficiency; however, clinical details were not provided, this variant was detected in the heterozygous state, and the potential of sample and clinical information misclassification was suggested (Kruger WD et al. Hum Mol Genet. 1995;4:1155-61). This variant was also detected in an individual from a coronary artery dissection cohort who had a second CBS variant (phase unknown), no typical disease features, and normal serum homocysteine levels (Kaadan MI et al. Circ Genom Precis Med. 2018;11:e001933). Studies have indicated that this variant results in reduced protein and enzyme activity in yeast assays (Kabil O et al. J Biol Chem. 1999;274:31256-60; Shan X et al. Hum Mol Genet. 2001;10:635-43; Singh LR et al. PLoS Genet. 2010;6:e1000807; Mayfield JA et al. Genetics. 2012;190:1309-23). This amino acid position is highly 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.
Invitae RCV000458159 SCV000543513 uncertain significance Classic homocystinuria 2016-12-08 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 168 of the CBS protein (p.Val168Met). The valine residue is moderately conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs121964970, ExAC 0.01%). This variant has been reported in a cell line from an individual supposedly with CBS deficiency, however, misclassification of pedigree relationships and clinical phenotype was suspected for this individual (PMID: 8528202). It has also been observed as compound heterozygous in an individual affected with hyperhomocysteinemia (Invitae). ClinVar contains an entry for this variant (Variation ID: 127). Experimental studies have shown that this variant results in reduced expression and loss of enzyme activity (PMID: 8528202, 22267502, 10531322, 20066033). In summary, this variant has been observed in the cell line of an individual with suspected homocystinuria, and has been shown to affect protein function. However, without additional genetic data, this variant has been classified as a Variant of Uncertain Significance.
Illumina Clinical Services Laboratory,Illumina RCV000458159 SCV001298058 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
OMIM RCV000000150 SCV000020293 pathogenic Homocystinuria, pyridoxine-responsive 2003-12-01 no assertion criteria provided literature only

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