ClinVar Miner

Submissions for variant NM_000071.3(CBS):c.325T>C (p.Cys109Arg)

gnomAD frequency: 0.00002  dbSNP: rs778220779
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000199752 SCV000249727 pathogenic not provided 2023-11-22 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 (PMID: 22267502, 12124992); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27959664, 12124992, 29326875, PramparoT2023[Abstract], 22267502)
Ambry Genetics RCV000248928 SCV000319354 pathogenic Cardiovascular phenotype 2014-08-13 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002229441 SCV000649832 pathogenic HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED 2023-12-20 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 109 of the CBS protein (p.Cys109Arg). This variant is present in population databases (rs778220779, gnomAD 0.003%). This missense change has been observed in individual(s) with homocystinuria (PMID: 12124992). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 212878). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CBS protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CBS function (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.
Eurofins Ntd Llc (ga) RCV000199752 SCV000700264 pathogenic not provided 2017-05-02 criteria provided, single submitter clinical testing
Baylor Genetics RCV000535881 SCV004213870 pathogenic Classic homocystinuria 2023-09-12 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000535881 SCV004847626 likely pathogenic Classic homocystinuria 2019-01-24 criteria provided, single submitter clinical testing The p.Cys109Arg variant in CBS has been reported in the compound heterozygous state in 3 individuals and in the heterozygous state in 1 individual with homocystinuria (Gaustadnes 2002, Voskoboeva 2018). It has also been identified in 3/113348 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In vitro functional studies support an impact on protein function (Mayfield 2012), though these studies may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive homocystinuria. ACMG/AMP Criteria applied: PM3_Strong, PM2, PS3_Moderate.
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
PreventionGenetics, part of Exact Sciences RCV004754347 SCV005360414 likely pathogenic CBS-related disorder 2024-06-15 no assertion criteria provided clinical testing The CBS c.325T>C variant is predicted to result in the amino acid substitution p.Cys109Arg. This variant has been reported with a second CBS variant in individuals with homocystinuria (Gaustadnes et al. 2002. PubMed ID: 12124992; Sweetser et al. 2016. PubMed ID: 27959664; Voskoboeva et al. 2017. PubMed ID: 29326875). This variant is reported in 0.0026% of alleles in individuals of European (non-Finnish) descent in gnomAD. In vivo experimental studies suggest this variant impacts protein function (Gaustadnes et al. 2002. PubMed ID: 12124992; Mayfield et al. 2012. PubMed ID: 22267502). This variant is interpreted as likely pathogenic.

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