ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.325T>C (p.Cys109Arg) (rs778220779)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000199752 SCV000249727 pathogenic not provided 2019-04-19 criteria provided, single submitter clinical testing In a yeast system lacking the CBS ortholog, expression of a construct with C109R showed a failure to restore function /rescue growth (Gaustadnes, 2002; Mayfield et al., 2012); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27959664, 22267502, 12124992, 29326875)
Ambry Genetics RCV000248928 SCV000319354 pathogenic Cardiovascular phenotype 2014-08-13 criteria provided, single submitter clinical testing
Invitae RCV000535881 SCV000649832 pathogenic Classic homocystinuria 2020-09-17 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 109 of the CBS protein (p.Cys109Arg). The cysteine residue is moderately conserved and there is a large physicochemical difference between cysteine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with homocystinuria, being observed on the opposite chromosome (in trans) from a pathogenic variant in an affected individual (PMID: 12124992). ClinVar contains an entry for this variant (Variation ID: 212878). Experimental studies have shown that this missense variant reduces CBS enzymatic activity in bacterial and yeast expression systems (PMID: 12124992, 22267502). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588375 SCV000695304 pathogenic Homocystinuria 2016-01-26 criteria provided, single submitter clinical testing Variant summary: The c.325T>C in CBS gene is a missense variant that involves a highly conserved nucleotide and 5/5 in silico tools predict deleterious outcome. The variant is absent from the broad control population dataset of ExAC, suggesting this variant is not a common polymorphism. The variant has been reported in several affected individuals presented with features suggestive of Cystathionine--synthase deficiency. Functional studies performed in yeast-based system showed conflicting results in experiments with B6 supplementation, low enzymatic activity and non-functional yeast phenotype. The variant of interest has been reported as Pathogenic by several reputable databases/diagnostic centers without providing evidence to independently evaluate. Taking together, the variant was classified as Pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000199752 SCV000700264 pathogenic not provided 2017-05-02 criteria provided, single submitter clinical testing
Counsyl RCV000535881 SCV000797245 likely pathogenic Classic homocystinuria 2018-01-17 no assertion criteria provided clinical testing
Natera, Inc. RCV000535881 SCV001452100 pathogenic Classic homocystinuria 2020-09-16 no assertion criteria provided clinical testing

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