ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.494G>A (p.Cys165Tyr) (rs1347651454)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000587735 SCV000695306 pathogenic Homocystinuria 2017-08-24 criteria provided, single submitter clinical testing Variant summary: The CBS c.494G>A (p.Cys165Tyr) variant causes a missense change involving the alteration of a conserved nucleotide located in the Tryptophan synthase beta subunit-like PLP-dependent enzyme domain.. 5/5 in silico tools predict a damaging outcome for this variant. An enzymatic assay using yeast showed non-functional CBS enzyme associated with this variant (Mayfield_2012), and in at least one patient homozygous for the variant, activity in fibroblasts was non-detectable (Kluijtmans_1999). This variant was not found in the large control database ExAC in 29004 control chromosomes and was reported in multiple patients with homocystinuria (Kluijtmans_1999, Magner_2011). Taken together, this variant is classified as pathogenic.
Ambry Genetics RCV000619758 SCV000738494 pathogenic Cardiovascular phenotype 2016-10-26 criteria provided, single submitter clinical testing Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous;2 of classification of c (below) met (2c = 1b);Deficient protein function by in vitro/ex vivo assay
Invitae RCV000801652 SCV000941440 pathogenic Classic homocystinuria 2018-10-09 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 165 of the CBS protein (p.Cys165Tyr). The cysteine residue is moderately conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be segregating with homocystinuria in a family and to be homozygous or in combination with another CBS variant in unrelated affected individuals (PMID: 7635485, 10215408, 12124992, 10364517, 18708589, 20567906). ClinVar contains an entry for this variant (Variation ID: 495531). Experimental studies have shown that this missense change decreases enzyme activity and function (PMID: 10215408, 22267502, 20506325, 20490928, 11359213). For these reasons, this variant has been classified as Pathogenic.

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