ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.636C>T (p.Asn212=) (rs2298758)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000254497 SCV000317311 benign Cardiovascular phenotype 2016-01-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: General population or sub-population frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
GeneDx RCV000124148 SCV000167562 benign not specified 2013-12-11 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Illumina Clinical Services Laboratory,Illumina RCV000281054 SCV000436222 uncertain significance Homocystinuria 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000124148 SCV000919085 benign not specified 2018-08-20 criteria provided, single submitter clinical testing Variant summary: CBS c.636C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0012 in 275734 control chromosomes, predominantly at a frequency of 0.015 within the East Asian subpopulation in the gnomAD database, including 7 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 5-fold of the estimated maximal expected allele frequency for a pathogenic variant in CBS causing Homocystinuria phenotype (0.003), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant, c.636C>T, has not been reported in the literature in individuals affected with Homocystinuria. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS x1, benign x2). Based on the evidence outlined above, the variant was classified as benign.
Invitae RCV000540728 SCV000649844 benign Homocystinuria due to CBS deficiency 2017-06-07 criteria provided, single submitter clinical testing

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