ClinVar Miner

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

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000248928 SCV000319354 pathogenic Cardiovascular phenotype 2014-08-13 criteria provided, single submitter clinical testing
Counsyl RCV000535881 SCV000797245 likely pathogenic Homocystinuria due to CBS deficiency 2018-01-17 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000199752 SCV000700264 pathogenic not provided 2017-05-02 criteria provided, single submitter clinical testing
GeneDx RCV000199752 SCV000249727 pathogenic not provided 2014-09-09 criteria provided, single submitter clinical testing p.Cys109Arg (TGT>CGT): c.325 T>C in exon 5 of the CBS gene (NM_000071.2). The C109R mutation in the CBS gene has been reported previously in association with homocystinuria due to CBS deficiency (Gaustadnes et al., 2002). Gaustadnes et al. identified C109R along with another mutation in the CBS gene in a 14 year-old Australian patient with CBS-deficiency and dislocated lenses. In vitro functional studies showed that C109R results in reduced CBS enzyme activity in yeast (Mayfield et al., 2012). C109R results in a semi-conservative amino acid substitution of a neutral, polar Cysteine with a positively charged Arginine. Mutations in nearby residues (K102N, K102Q, A114V) have been reported in association with homocystinuria, further supporting the functional importance of this region of the protein. Additionally, the C109R mutation was not observed in approximately 6500 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, C109R in the CBS gene is interpreted as a disease-causing mutation. This variant was found in TAAD,CBS
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000535881 SCV000649832 pathogenic Homocystinuria due to CBS deficiency 2018-12-17 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.

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