ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.856A>G (p.Ile286Val) (rs147040567)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000731875 SCV000249695 uncertain significance not provided 2018-11-13 criteria provided, single submitter clinical testing The I286V variant of uncertain significance in the CBS gene has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 29/256,192 (0.01%) alleles globally, from individuals in large population cohorts (Lek et al., 2016). The I286V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000648120 SCV000769932 uncertain significance Homocystinuria due to CBS deficiency 2018-12-19 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 286 of the CBS protein (p.Ile286Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs147040567, ExAC 0.02%). This variant has not been reported in the literature in individuals with CBS-related disease. ClinVar contains an entry for this variant (Variation ID: 212855). 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 and their clinical significance is uncertain. 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.
Geisinger Autism and Developmental Medicine Institute,Geisinger Health System RCV000648120 SCV000804339 uncertain significance Homocystinuria due to CBS deficiency 2017-10-06 criteria provided, single submitter provider interpretation This 6 year old male with global developmental delays is a compound heterozygote for 2 VUSs in the CBS gene (p.Glu283Lys and p.Ile286Val). The p.Ile286Val variant is present in the gnomAD non-Finnish European population at a frequency of 0.02%. Computational models predict it to benign. He has normal stature (30%tile). Subsequent clinical testing showed normal plasma homocysteine and methionine levels.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000731875 SCV000859738 uncertain significance not provided 2018-02-19 criteria provided, single submitter clinical testing

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