ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.400G>A (p.Gly134Arg) (rs147474549)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000196511 SCV000249728 uncertain significance not provided 2018-06-05 criteria provided, single submitter clinical testing The G134R variant of uncertain significance in the CBS gene has been identified in the CBS gene has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The G134R 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. Additionally, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000469139 SCV000543500 uncertain significance Classic homocystinuria 2019-12-09 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 134 of the CBS protein (p.Gly134Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs147474549, ExAC 0.1%) but has not been reported in the literature in individuals with a CBS-related disease. ClinVar contains an entry for this variant (Variation ID: 212879). 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, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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