ClinVar Miner

Submissions for variant NM_001360.3(DHCR7):c.98+2_98+6del

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001235655 SCV001408349 likely pathogenic Smith-Lemli-Opitz syndrome 2019-09-20 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 3 of the DHCR7 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with Smith–Lemli–Opitz syndrome (PMID: 23042628). 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 DHCR7 are known to be pathogenic (PMID: 9634533, 10677299). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001235655 SCV001623357 likely pathogenic Smith-Lemli-Opitz syndrome 2021-04-20 criteria provided, single submitter clinical testing Variant summary: DHCR7 c.98+2_98+6delTAAGG 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: Four predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251496 control chromosomes. c.98+2_98+6delTAAGG has been reported in the literature in at-least one individual affected with Smith-Lemli-Opitz Syndrome and has been subsequently cited by others (example, Waterham_2012, Bianconi_2015). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic citing an overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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