ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.394C>T (p.Arg132Cys) (rs140002610)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000195820 SCV000249679 uncertain significance not specified 2017-06-01 criteria provided, single submitter clinical testing The R132C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. Although this variant has previously been observed in other unrelated individuals referred for Marfan/TAAD genetic testing at GeneDx, none of these individuals harbored a second variant in the CBS gene, as would be expected for an autosomal recessive disorder. The R132C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In addition, in silico analysis predicts this variant is probably damaging to the protein structure/function. However, this substitution occurs at a position that is not conserved across species. Furthermore, the NHLBI Exome Sequencing Project and the Exome Aggregation Consortium (ExAC) report R132C was observed in 6/8,600 alleles from individuals of European background and 6/8,570 alleles from individuals of East Asian background, respectively.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000726351 SCV000344004 uncertain significance not provided 2016-08-09 criteria provided, single submitter clinical testing
Invitae RCV000460928 SCV000543519 uncertain significance Classic homocystinuria 2019-11-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 132 of the CBS protein (p.Arg132Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs140002610, ExAC 0.07%). This variant has not been reported in the literature in individuals with CBS-related disease. ClinVar contains an entry for this variant (Variation ID: 212843). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; 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.
Ambry Genetics RCV000620847 SCV000738480 uncertain significance Cardiovascular phenotype 2017-05-24 criteria provided, single submitter clinical testing Insufficient evidence
Counsyl RCV000460928 SCV000797533 uncertain significance Classic homocystinuria 2018-02-05 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000726351 SCV000885145 uncertain significance not provided 2018-01-30 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000460928 SCV001298059 uncertain significance Classic homocystinuria 2017-09-05 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille RCV001252179 SCV001427929 uncertain significance Intellectual disability 2019-01-01 no assertion criteria provided clinical testing

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