ClinVar Miner

Submissions for variant NM_001360.2(DHCR7):c.1348del (p.Arg450fs) (rs886042362)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000725059 SCV000333636 likely pathogenic not provided 2015-08-11 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000316051 SCV001572441 likely pathogenic Smith-Lemli-Opitz syndrome 2021-04-01 criteria provided, single submitter clinical testing Variant summary: DHCR7 c.1348delC (p.Arg450AlafsX31) located in the last exon (exon 9) causes a frameshift which results in an extension of the protein. The variant was absent in 248600 control chromosomes. c.1348delC has been reported in the literature in one heterozygous individual who had a near normal ratio of fractional choloesterol synthesis (Wassif_2005). These report(s) do not provide unequivocal conclusions about association of the variant with Smith-Lemli-Opitz Syndrome. 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. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000316051 SCV001576443 likely pathogenic Smith-Lemli-Opitz syndrome 2020-10-20 criteria provided, single submitter clinical testing This sequence change results in a frameshift in the DHCR7 gene (p.Arg450Alafs*31). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 26 amino acids of the DHCR7 protein and extend the protein by an additional 4 amino acids. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with DHCR7-related conditions. ClinVar contains an entry for this variant (Variation ID: 282268). This variant disrupts the p.Arg450 amino acid residue in DHCR7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22391996, 25405082,15896653, 16181459, 10405455). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
GeneDx RCV000725059 SCV001784580 likely pathogenic not provided 2019-08-12 criteria provided, single submitter clinical testing Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 26 amino acids are lost and replaced with 30 incorrect amino acids; Not observed in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge
Counsyl RCV000316051 SCV000800696 uncertain significance Smith-Lemli-Opitz syndrome 2018-04-20 no assertion criteria provided clinical testing

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