ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.737-1G>C (rs757428597)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000544919 SCV000649847 pathogenic Classic homocystinuria 2019-10-23 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 8 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 (rs757428597, ExAC 0.002%). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with homocystinuria (PMID: 14635102). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 471366). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Counsyl RCV000544919 SCV000797640 likely pathogenic Classic homocystinuria 2018-02-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001260387 SCV001437348 likely pathogenic Homocystinuria 2020-09-21 criteria provided, single submitter clinical testing Variant summary: CBS c.737-1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.3e-06 in 241320 control chromosomes. c.737-1G>C has been reported in the literature in at least one individual affected with Homocystinuria (Kruger_2003). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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