ClinVar Miner

Submissions for variant NM_000071.3(CBS):c.670C>T (p.Arg224Cys)

gnomAD frequency: 0.00013  dbSNP: rs139456571
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000726462 SCV000249689 uncertain significance not provided 2021-03-16 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics RCV002310758 SCV000318560 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2024-03-28 criteria provided, single submitter clinical testing The p.R224C variant (also known as c.670C>T), located in coding exon 6 of the CBS gene, results from a C to T substitution at nucleotide position 670. The arginine at codon 224 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.
Eurofins Ntd Llc (ga) RCV000726462 SCV000344856 uncertain significance not provided 2016-08-15 criteria provided, single submitter clinical testing
Invitae RCV002517164 SCV000649845 uncertain significance HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED 2022-08-18 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 224 of the CBS protein (p.Arg224Cys). This variant is present in population databases (rs139456571, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with CBS-related conditions. ClinVar contains an entry for this variant (Variation ID: 212851). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Mayo Clinic Laboratories, Mayo Clinic RCV000726462 SCV001715597 uncertain significance not provided 2021-03-30 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000726462 SCV001748029 uncertain significance not provided 2021-06-01 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000556147 SCV001781421 uncertain significance Classic homocystinuria 2021-07-14 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003330558 SCV004039504 uncertain significance not specified 2023-08-15 criteria provided, single submitter clinical testing Variant summary: CBS c.670C>T (p.Arg224Cys) results in a non-conservative amino acid change located in the Tryptophan synthase beta chain-like, PALP domain (IPR001926) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 251364 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CBS causing Homocystinuria (0.00021 vs 0.003), allowing no conclusion about variant significance. c.670C>T has been reported in the literature in individuals affected with Neurodevelopmental Disorders (Popp_2017). This report does not provide unequivocal conclusions about association of the variant with Homocystinuria. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 29158550). Eight ClinVar submitters have assessed the variant since 2014, and all submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc. RCV000556147 SCV001462124 uncertain significance Classic homocystinuria 2020-09-16 no assertion criteria provided clinical testing

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