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

Total submissions: 5

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