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

Total submissions: 6

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	Homocystinuria due to CBS deficiency	2018-11-30	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	Lines of evidence used in support of classification: Insufficient evidence
Counsyl	RCV000460928	SCV000797533	uncertain significance	Homocystinuria due to CBS deficiency	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