ClinVar Miner

Submissions for variant NM_000071.3(CBS):c.856A>G (p.Ile286Val)

gnomAD frequency: 0.00020  dbSNP: rs147040567
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Total submissions: 8
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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 RCV002517999 SCV000769932 uncertain significance HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED 2022-07-25 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 286 of the CBS protein (p.Ile286Val). This variant is present in population databases (rs147040567, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CBS-related conditions. 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. 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 Classic homocystinuria 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.
Eurofins Ntd Llc (ga) RCV000731875 SCV000859738 uncertain significance not provided 2018-02-19 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000648120 SCV001303266 uncertain significance Classic homocystinuria 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Ambry Genetics RCV002444786 SCV002680385 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2023-05-17 criteria provided, single submitter clinical testing The p.I286V variant (also known as c.856A>G), located in coding exon 8 of the CBS gene, results from an A to G substitution at nucleotide position 856. The isoleucine at codon 286 is replaced by valine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV000648120 SCV002777121 uncertain significance Classic homocystinuria 2021-10-14 criteria provided, single submitter clinical testing
Natera, Inc. RCV000648120 SCV001462115 uncertain significance Classic homocystinuria 2020-09-16 no assertion criteria provided clinical testing

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