Submissions for variant NM_001360.3(DHCR7):c.1055G>A (p.Arg352Gln)

dbSNP: rs121909768

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254828	SCV000321550	pathogenic	not provided	2021-06-30	criteria provided, single submitter	clinical testing	Published functional studies demonstrate reduced protein expression compared to wild-type (Prabhu et al., 2016); 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; In addition, in silico splice predictors suggest this variant may lead to abnormal gene splicing; This variant is associated with the following publications: (PMID: 22975760, 16044199, 27401223, 27415407, 28166604, 21696385, 20556518, 18006960, 17441222, 9653161, 15521979, 27535533, 33836803, 26887953, 10677299)
Eurofins Ntd Llc (ga)	RCV000254828	SCV000331534	pathogenic	not provided	2015-07-31	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000007197	SCV000893239	pathogenic	Smith-Lemli-Opitz syndrome	2022-02-10	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000007197	SCV001194167	pathogenic	Smith-Lemli-Opitz syndrome	2019-12-17	criteria provided, single submitter	clinical testing	NM_001360.2(DHCR7):c.1055G>A(R352Q) is classified as pathogenic in the context of Smith-Lemli-Opitz syndrome and is associated with moderate or mild forms of this disease. Sources cited for classification include the following: PMID 16044199, 21696385, 20556518, 10677299 and 17441222. Classification of NM_001360.2(DHCR7):c.1055G>A(R352Q) is based on the following criteria: This is a well-established pathogenic variant in the literature that 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000007197	SCV001572442	pathogenic	Smith-Lemli-Opitz syndrome	2021-04-01	criteria provided, single submitter	clinical testing	Variant summary: DHCR7 c.1055G>A (p.Arg352Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 248990 control chromosomes. c.1055G>A has been reported in the literature in multiple individuals affected with Smith-Lemli-Opitz Syndrome (example, Witsch-Baumgartner_2000, Matsumoto_2005). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in an approximately 75% reduction of DHCR7 protein stability that is rescued upon statin treatment (example, Prabhu_2016). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000007197	SCV001581349	pathogenic	Smith-Lemli-Opitz syndrome	2023-12-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 352 of the DHCR7 protein (p.Arg352Gln). This variant is present in population databases (rs121909768, gnomAD 0.01%). This missense change has been observed in individual(s) with DHCR7-related conditions (PMID: 10677299, 21696385). ClinVar contains an entry for this variant (Variation ID: 6795). 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.Arg352 amino acid residue in DHCR7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9653161, 15521979, 18006960; Invitae). 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.
OMIM	RCV000007197	SCV000027393	pathogenic	Smith-Lemli-Opitz syndrome	2005-01-01	no assertion criteria provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000254828	SCV001742879	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000254828	SCV001951057	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000007197	SCV002093014	pathogenic	Smith-Lemli-Opitz syndrome	2017-03-17	no assertion criteria provided	clinical testing