Submissions for variant NM_001360.3(DHCR7):c.724C>T (p.Arg242Cys)

gnomAD frequency: 0.00012  dbSNP: rs80338856

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000389331	SCV000329334	pathogenic	not provided	2025-04-05	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26969503, 22975760, 28166604, 27415407, 11175299, 10677299, 16207203, 12070263, 10405455, 10995508, 27401223, 23042628, 15464432, 15954111, 28250423, 30609409, 31589614, 34308104, 37924809)
Eurofins Ntd Llc (ga)	RCV000389331	SCV000331535	pathogenic	not provided	2015-09-08	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000020438	SCV000373917	pathogenic	Smith-Lemli-Opitz syndrome	2017-04-27	criteria provided, single submitter	clinical testing	Across a selection of available literature, the DHCR7 c.724C>T (p.Arg242Cys) missense variant has been identified in a compound heterozygous state in at least six individuals with Smith-Lemli-Opitz syndrome and in two additional patients with unknown zygosity (Neklason et al. 1999; Krakowiak et al. 2000; Witsch-Baumgartner et al. 2000; Waye et al. 2005; Tucci et al. 2016). In a review, Boland et al. (2016) report that the p.Arg242Cys variant was found in 12 out of 1037 (1.2%) patient alleles across 30 studies. The p.Arg242Cys variant was absent from 50 controls and is reported at a frequency of 0.00029 in the African population of the Exome Aggregation. Functional studies demonstrated that the enzymatic activity in fibroblasts derived from a patient who was compound heterozygous for the p.Arg242Cys variant and another missense variant was significantly reduced (Ginat et al. 2004). Based on the evidence, the p.Arg242Cys variant is classified as pathogenic for Smith-Lemli-Opitz syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000020438	SCV000697848	pathogenic	Smith-Lemli-Opitz syndrome	2016-08-04	criteria provided, single submitter	clinical testing	Variant summary: The DHCR7 c.724C>T (p.Arg242Cys) variant located in the transmembrane domain causes a missense change involving a conserved nucleotide with 5/5 in silico tools predicting a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 10/121036 (1/12106), which does not exceed the maximal expected allele frequency for a pathogenic DHCR7 variant of 1/230. The variant of interest has been reported in multiple affected individuals via publications. In addition, GeneReviews cites the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000020438	SCV000711726	likely pathogenic	Smith-Lemli-Opitz syndrome	2015-09-11	criteria provided, single submitter	clinical testing	The p.Arg242Cys (NM_000060.2 c.724C>T) variant in DHCR7 has been reported in at least 6 individuals with clinical features of Smith-Lemli-Opitz syndrome who wer e compound heterozygotes for a second DHCR7 variant, and segregated with disease in one affected family member (Neklason 1999, Krakowiak 2000, Waye 2002, Correa -Cerro 2005, Waye 2005, Tucci 2016). This variant has also been identified in 19 /126,670 of European chromosomes by the Genome Aggregation Database (gnomAD, htt p://gnomad.broadinstitute.org; dbSNP rs80338856). Although this variant has been seen in the general population, its frequency is low enough to be consistent wi th a recessive carrier frequency. In vitro functional studies provide some evide nce that the p.Arg242Cys variant may impact protein function (Neklason 1999). In summary, although additional studies are required to fully establish its clinic al significance, the p.Arg242Cys variant is likely pathogenic for Smith-Lemli-Op itz syndrome in an autosomal recessive manner based on its occurrence in affecte d individuals, low frequency in controls, and functional data.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000020438	SCV000825551	pathogenic	Smith-Lemli-Opitz syndrome	2024-12-06	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 242 of the DHCR7 protein (p.Arg242Cys). This variant is present in population databases (rs80338856, gnomAD 0.02%). This missense change has been observed in individuals with Smith-Lemli-Opitz syndrome (PMID: 10405455, 10677299, 10995508, 15464432, 15954111, 26969503). ClinVar contains an entry for this variant (Variation ID: 21275). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt DHCR7 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects DHCR7 function (PMID: 15464432). This variant disrupts the p.Arg242 amino acid residue in DHCR7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10995508, 11427181, 12818773, 15776424, 16044199). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000020438	SCV000893242	pathogenic	Smith-Lemli-Opitz syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000020438	SCV001163328	pathogenic	Smith-Lemli-Opitz syndrome		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000020438	SCV001193935	likely pathogenic	Smith-Lemli-Opitz syndrome	2019-12-04	criteria provided, single submitter	clinical testing	NM_001360.2(DHCR7):c.724C>T(R242C) is classified as likely pathogenic in the context of Smith-Lemli-Opitz syndrome. Sources cited for classification include the following: PMID 10677299, 15954111, 10995508, 18076100, 10405455, and 16983147. Classification of NM_001360.2(DHCR7):c.724C>T(R242C) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Revvity Omics, Revvity	RCV000020438	SCV002020376	pathogenic	Smith-Lemli-Opitz syndrome	2019-09-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002371778	SCV002670250	pathogenic	Inborn genetic diseases	2021-08-19	criteria provided, single submitter	clinical testing	The c.724C>T (p.R242C) alteration is located in exon 7 (coding exon 5) of the DHCR7 gene. This alteration results from a C to T substitution at nucleotide position 724, causing the arginine (R) at amino acid position 242 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of 0.01% (27/282746) total alleles studied. The highest observed frequency was 0.02% (4/24962) of African alleles. This mutation was identified in multiple individuals with Smith-Lemli-Opitz syndrome (SLOS) (Neklason, 1999; Krakowiak, 2000; Ginat, 2004; Waye, 2005; Tucci, 2016; Saskin, 2017). This amino acid position is highly conserved in available vertebrate species. Enzyme activity in a cell line from an individual with SLOS with this mutation demonstrated reduced activity (Ginat, 2004). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000020438	SCV005051749	pathogenic	Smith-Lemli-Opitz syndrome	2024-02-01	criteria provided, single submitter	curation
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000020438	SCV005875392	pathogenic	Smith-Lemli-Opitz syndrome	2024-05-21	criteria provided, single submitter	clinical testing	The DHCR7 c.724C>T; p.Arg242Cys variant (rs80338856; ClinVar ID: 21275) is reported in the literature in multiple individuals affected with Smith-Lemli-Opitz syndrome, many of whom carry an additional pathogenic DHCR7 variant (Boland 2016, Correa-Cerro 2005, Ginat 2004, Neklason 1999, Tucci 2016, Waye 2005). This variant is found in the general population with an overall allele frequency of 0.01% (27/282,746 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is deleterious (REVEL: 0.951). The p.Arg242Cys variant occurs in transmembrane domain 5 where multiple other pathogenic variants occur (Correa-Cerro 2005), and patient cells with the p.Arg242Cys variant exhibit reduced enzymatic activity (Ginat 2004, Neklason 1999). Based on available information, this variant is considered to be pathogenic. References: Boland MR and Tatonetti NP. Investigation of 7-dehydrocholesterol reductase pathway to elucidate off-target prenatal effects of pharmaceuticals: a systematic review. Pharmacogenomics J. 2016 Oct;16(5):411-29. PMID: 27401223. Correa-Cerro LS and Porter FD. 3beta-hydroxysterol Delta7-reductase and the Smith-Lemli-Opitz syndrome. Mol Genet Metab. 2005 Feb;84(2):112-26. PMID: 15670717. Ginat S et al. Lowered DHCR7 activity measured by ergosterol conversion in multiple cell types in Smith-Lemli-Opitz syndrome. Mol Genet Metab. 2004 Sep-Oct;83(1-2):175-83. PMID: 15464432. Neklason DW et al. Biochemical variants of Smith-Lemli-Opitz syndrome. Am J Med Genet. 1999 Aug 27;85(5):517-23. PMID: 10405455. Tucci A et al. The p.Phe174Ser mutation is associated with mild forms of Smith Lemli Opitz Syndrome. BMC Med Genet. 2016 Mar 11;17:22. PMID: 26969503. Waye JS et al. Identification of nine novel DHCR7 missense mutations in patients with Smith-Lemli-Opitz syndrome (SLOS). Hum Mutat. 2005 Jul;26(1):59. PMID: 15954111.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000020438	SCV005912830	pathogenic	Smith-Lemli-Opitz syndrome	2023-03-06	criteria provided, single submitter	research
GeneReviews	RCV000020438	SCV000040852	not provided	Smith-Lemli-Opitz syndrome		no assertion provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004748531	SCV005358886	pathogenic	DHCR7-related disorder	2024-06-17	no assertion criteria provided	clinical testing	The DHCR7 c.724C>T variant is predicted to result in the amino acid substitution p.Arg242Cys. This variant has been reported in multiple Smith-Lemli-Opitz syndrome (SLOS) patients (e.g., Neklason et al. 1999. PubMed ID: 10405455; Krakowiak et al. 2000. PubMed ID: 10995508; Witsch-Baumgartner et al. 2001. PubMed ID: 11175299; Tucci et al. 2016. PubMed ID: 26969503). The p.Arg242 amino acid is found in the 5th membrane-associated helix of the DHCR7 protein (Waterham and Hennekam. 2012. PubMed ID: 23042628) and the p.Arg242Cys amino acid substitution has resulted in decreased enzyme activity in experimental studies (Witsch-Baumgartner et al. 2000. PubMed ID: 10677299). In addition, a different substitution at the same location has also been reported in SLOS patients (e.g., Krakowiak et al. 2000. PubMed ID: 10995508). This variant is reported in 0.016% of alleles in individuals of African descent in gnomAD. Based on these observations, we classify the c.724C>T (p.Arg242Cys) variant as pathogenic.