ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.401G>C (p.Gly134Ala) (rs766958673)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000198867 SCV000249681 uncertain significance not provided 2014-01-11 criteria provided, single submitter clinical testing p.Gly134Ala (GGG>GCG): c.401 G>C in exon 5 of the CBS gene (NM_000071.2). The G134A variant in the CBS gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The G134 residue is highly conserved across species and in silico analysis predicts G134A is damaging to the protein structure/function. The G134A variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Missense mutations in nearby residues (E128D, E131D, G139R) have been reported in association with homocystinuria, supporting the functional importance of this region of the protein. However, G134A is a conservative amino acid substitution as these residues share similar properties, and are least likely to impact secondary structure. With the clinical and molecular information available at this time, we cannot definitively determine if G134A is a disease-causing mutation or a rare benign variant. This variant was found in TAAD
Invitae RCV001231415 SCV001403935 uncertain significance Classic homocystinuria 2019-08-22 criteria provided, single submitter clinical testing This sequence change replaces glycine with alanine at codon 134 of the CBS protein (p.Gly134Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CBS-related conditions. ClinVar contains an entry for this variant (Variation ID: 212845). 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: "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.

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