Submissions for variant NM_001360.3(DHCR7):c.725G>A (p.Arg242His)

gnomAD frequency: 0.00004  dbSNP: rs80338857

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000020439	SCV000697857	pathogenic	Smith-Lemli-Opitz syndrome	2017-03-10	criteria provided, single submitter	clinical testing	Variant summary: The DHCR7 c.725G>A (p.Arg242His) variant located in the transmembrane domain involves the alteration of a conserved nucleotide and is predicted to be damaging by 5/5 in silico tools. This variant was found in 27/569654 control chromosomes (all heterozygotes) including ExAC at a frequency of 0.0000474, which does not exceed the estimated maximal expected allele frequency of a pathogenic DHCR7 variant (0.0043301). This variant is one of twelve frequent mutations causing SmithLemliOpitz syndrome (Bianconi_2015) and is reported in at least five independent patients with SmithLemliOpitz syndrome in compound heterozygous state with another pathogenic/likely pathogenic variants (Krakowiak_2001, Jira_2001, Witsch-Baumgartner _2001, Matsumoto_2005, Wassif_2005, Li_2016). Biochemical analysis of DHC and cholesterol levels as well as enzymatic evaluation in fibroblast cells from patients with this variant is supportive of functional impairment due this variant. Another missense change at this residue p.Arg242Cys is a known pathogenic variant, further highlighting functional significance of this residue. In addition, multiple reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Invitae	RCV000020439	SCV000829407	pathogenic	Smith-Lemli-Opitz syndrome	2023-12-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 242 of the DHCR7 protein (p.Arg242His). This variant is present in population databases (rs80338857, gnomAD 0.005%). This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome and combined with other DHCR7 variants in several individuals with this condition (PMID: 10995508, 11427181, 12818773, 15776424, 16044199). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 21276). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DHCR7 protein function with a positive predictive value of 95%. 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: 10405455, 10677299, 10995508, 15464432, 15954111, 26969503). 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.
Baylor Genetics	RCV000020439	SCV001163702	likely pathogenic	Smith-Lemli-Opitz syndrome		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000020439	SCV001194236	likely pathogenic	Smith-Lemli-Opitz syndrome	2019-12-20	criteria provided, single submitter	clinical testing	NM_001360.2(DHCR7):c.725G>A(R242H) is classified as likely pathogenic in the context of Smith-Lemli-Opitz syndrome. Sources cited for classification include the following: PMID 16044199, 11427181, 12818773, 23293579 and 10995508. Classification of NM_001360.2(DHCR7):c.725G>A(R242H) 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.‚Äã
GeneDx	RCV001529736	SCV001777313	pathogenic	not provided	2023-04-04	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 16207203, 11427181, 22975760, 23319240, 10995508, 16044199, 20301322, 29961769, 28166604, 27415407, 23293579, 15776424, 31589614)
Fulgent Genetics, Fulgent Genetics	RCV000020439	SCV002811486	likely pathogenic	Smith-Lemli-Opitz syndrome	2021-11-08	criteria provided, single submitter	clinical testing
Lifecell International Pvt. Ltd	RCV000020439	SCV003930272	likely pathogenic	Smith-Lemli-Opitz syndrome		criteria provided, single submitter	clinical testing	A Heterozygous Missense variant c.725G>A in Exon 7 of the DHCR7 gene that results in the amino acid substitution p.Arg242His was identified. The observed variant has a maximum allele frequency of 0.00002/0.00006% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic/ Likely Pathogenic [Variant ID: 21276]. The observed variant has been previously reported in patients affected with Smith-Lemli-Opitz syndrome (Balogh, I et al., 2012). Furthermore, experimental studies showed the variant disrupts the DHCR7 protein function (Neklason, D W et al., 1999). For these reasons, this variant has been classified as Likely Pathogenic.
GeneReviews	RCV000020439	SCV000040853	not provided	Smith-Lemli-Opitz syndrome		no assertion provided	literature only
SingHealth Duke-NUS Institute of Precision Medicine	RCV000020439	SCV000853128	likely pathogenic	Smith-Lemli-Opitz syndrome	2017-06-07	no assertion criteria provided	curation
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529736	SCV001743704	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001529736	SCV001807235	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001529736	SCV001972084	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000020439	SCV002093031	pathogenic	Smith-Lemli-Opitz syndrome	2017-03-16	no assertion criteria provided	clinical testing