ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.296T>A (p.Phe99Tyr) (rs112029370)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000459701 SCV000543516 uncertain significance Classic homocystinuria 2019-11-20 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with tyrosine at codon 99 of the CBS protein (p.Phe99Tyr). The phenylalanine residue is weakly conserved and there is a small physicochemical difference between phenylalanine and tyrosine. This variant is present in population databases (rs112029370, ExAC 0.1%) but 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 rare missense change that is not predicted to affect protein function, and 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.
GeneDx RCV000497848 SCV000589389 uncertain significance not specified 2017-06-02 criteria provided, single submitter clinical testing The F99Y variant of uncertain significance in the CBS gene has not been published as pathogenic or benign to our knowledge. This variant has been observed in up to 0.2% of alleles from individuals of African or African American backgrounds in large population cohorts, although no homozygous individuals have been reported (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The F99Y variant has also been identified in multiple individuals referred for connective tissue disorder genetic testing at GeneDx; however, no second variants in the CBS gene were identified. The F99Y 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. Nevertheless, this substitution occurs at a position that is not conserved across species, and Y99 is tolerated in at least two species. Moreover, in silico analysis predicts F99Y likely does not alter the protein structure/function.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000497848 SCV000602919 uncertain significance not specified 2016-08-16 criteria provided, single submitter clinical testing

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