ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.622T>C (p.Trp208Arg) (rs1060500683)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000457277 SCV000543507 uncertain significance Homocystinuria due to CBS deficiency 2017-06-27 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with arginine at codon 208 of the CBS protein (p.Trp208Arg). The tryptophan residue is moderately conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a CBS-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786286 SCV000925046 uncertain significance not provided 2016-08-11 no assertion criteria provided provider interpretation The patient had genetic testing which included sequencing of 22 genes associated with aneurysms and dissections and related conditions: ACTA2, CBS, COL3A1, COL5A1, COL5A2, FBN1, FBN2, FLNA, MED12, MYH11, MYLK, NOTCH1, PRKG1, SKI, SLC2A10, SMAD3, SMAD4, SMAD6, TGFB2, TGFB3, TGFBR1 and TGFBR2. Results show that no disease-causing variants were found. See report below. p.Trp208Arg (c.622T>C) in the CBS gene (NM_000090.3) The lab this variant as a variant of unknown significance. Given a lack of case data and software predictions that this variant is likely tolerated, we consider this variant of unknown significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This variant has not been seen previously in the literature or databases of CBS DNA variants. S217F is the nearest missense variant that has been listed as pathogenic in clinvar. There are variants at 206, 204 and 212 which are listed as variants of unknown significance in clinvar. In silico analysis with PolyPhen-2 predicts the variant to be benign (HumVar: 0.010). The Trp at codon 208 is weakly conserved across species with W208Q and W208L being the alternate isoforms at that position. This variant falls in a helix domain from aa 203-213. There is variation at codon 208 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~60,000 individuals of European, African, Latino and Asian descent at this position (as of August 11, 2016). The average coverage at that site in ExAC is 30x. This individual has a Trp208Cys missense change at that position.

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