ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.828+1G>A (rs763290176)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000673023 SCV000798187 pathogenic Homocystinuria due to CBS deficiency 2018-02-27 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000673023 SCV000898571 likely pathogenic Homocystinuria due to CBS deficiency 2018-02-13 criteria provided, single submitter clinical testing CBS NM_000071.2 exon 9 c.828+1G>A: This variant has been reported in the literature as a compound heterozygote in 1 individual with homocystinuria (Kraus 1999 PMID:10338090). This variant is present in 2/110146 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs763290176). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population and/or variable expressivity. Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, this variant alters the consensus splice sequence (+/- 1,2) which is predicted to result in an absent or abnormal protein. Loss of function variants have been reported in association with disease for this gene (Kraus 1999 PMID:10338090). In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant is classified as likely pathogenic.
Invitae RCV000673023 SCV000961094 pathogenic Homocystinuria due to CBS deficiency 2018-09-12 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 9 of the CBS gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs763290176, ExAC 0.002%). This variant has been observed in individuals affected with homocystinuria (PMID: 15365998, 29352562). This variant is also known as IVS7+1G>A, 8297G>A in the literature. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CBS are known to be pathogenic (PMID: 10338090, 12124992). For these reasons, this variant has been classified as Pathogenic.

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