ClinVar Miner

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

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000250042 SCV000317362 pathogenic Cardiovascular phenotype 2014-11-20 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000179250 SCV000231470 uncertain significance not provided 2017-08-29 criteria provided, single submitter clinical testing
GeneDx RCV000179250 SCV000249683 pathogenic not provided 2015-04-29 criteria provided, single submitter clinical testing p.Val168Met (V168M) GTG>ATG: c.502 G>A in exon 6 of the CBS gene (NM_000071.2). The V168M mutation in the CBS gene has been reported as a heterozygous mutation in one individual with a clinical phenotype suggestive of homocystinuria (Kruger et al., 1995). Functional studies in yeast have also suggested that V168M results in a non-functional allele (Mayfield et al., 2012). Although, V168M results in a conservative amino acid substitution, it occurs at a position that is conserved across species. Mutations in the same residue (V168A) and in nearby residues (A155T A155V, A158V, C165Y, M173V, E176K) have been reported in association with homocystinuria, further supporting the functional importance of this region of the protein. Furthermore, the V168M mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, V168M in the CBS gene is interpreted as a disease-causing mutation. This variant was found in TAADV2-PANCARD
Invitae RCV000458159 SCV000543513 uncertain significance Homocystinuria due to CBS deficiency 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.
OMIM RCV000000150 SCV000020293 pathogenic Homocystinuria, pyridoxine-responsive 2003-12-01 no assertion criteria provided literature only

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