Submissions for variant NM_001360.3(DHCR7):c.1348del (p.Arg450fs)

dbSNP: rs886042362

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000316051	SCV001576443	pathogenic	Smith-Lemli-Opitz syndrome	2024-12-08	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 acid(s) of the DHCR7 protein and extend the protein by 4 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DHCR7-related conditions. ClinVar contains an entry for this variant (Variation ID: 282268). This variant disrupts a region of the DHCR7 protein in which other variant(s) (p.Arg450Leu) have been determined to be pathogenic (PMID: 10405455, 15896653, 16181459, 22391996, 25405082). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000725059	SCV001784580	likely pathogenic	not provided	2023-11-01	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 (gnomAD); Has not been previously published as pathogenic or benign to our knowledge
Fulgent Genetics, Fulgent Genetics	RCV000316051	SCV002813917	likely pathogenic	Smith-Lemli-Opitz syndrome	2024-05-25	criteria provided, single submitter	clinical testing
Counsyl	RCV000316051	SCV000800696	uncertain significance	Smith-Lemli-Opitz syndrome	2018-04-20	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000316051	SCV002092993	likely pathogenic	Smith-Lemli-Opitz syndrome	2019-12-23	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004748687	SCV005351378	likely pathogenic	DHCR7-related disorder	2024-07-18	no assertion criteria provided	clinical testing	The DHCR7 c.1348delC variant is predicted to result in a frameshift and premature protein termination (p.Arg450Alafs*31). To our knowledge, this variant has not been reported in the literature in any affected individuals. It is absent from large population database, indicating this variant is rare. This variant is not expected to lead to nonsense-mediated mRNA decay (NMD), but it is predicted to disrupt the terminal 26 amino acids of the DHCR7 and extend the protein by an additional 4 amino acids. Multiple changes downstream of this variant, such as premature termination, stop loss/extension, and missense variants, have been reported in association with Smith-Lemli-Opitz syndrome (SLOS) (Yan et al. 2019. PubMed ID: 31088393; Matsumoto et al. 2005. PubMed ID: 16044199; Witsch-Baumgartner et al. 2005. PubMed ID: 15776424). Taken together, the c.1348del (p.Arg450Alafs*31) variant is interpreted as likely pathogenic.