Submissions for variant NM_001360.3(DHCR7):c.278C>T (p.Thr93Met)

gnomAD frequency: 0.00009  dbSNP: rs80338853

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000079651	SCV000230167	pathogenic	not provided	2013-08-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000079651	SCV000512799	pathogenic	not provided	2021-07-01	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 10995508, 27535533, 24077912, 31178897, 16207203, 15670717, 10602371, 10677299, 11175299, 15776424, 17965227, 22211794, 14981719, 16446309, 9653161, 15952211, 22975760)
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000454251	SCV000537962	likely pathogenic	Abnormal brain morphology		criteria provided, single submitter	research
Invitae	RCV000007185	SCV000630074	pathogenic	Smith-Lemli-Opitz syndrome	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 93 of the DHCR7 protein (p.Thr93Met). This variant is present in population databases (rs80338853, gnomAD 0.008%). This missense change has been observed in individual(s) with Smith–Lemli–Opitz syndrome (PMID: 9653161, 10602371, 10677299, 10995508, 14981719, 15776424). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Mediterranean ancestry (PMID: 9653161, 10602371, 10677299, 10995508, 14981719, 15776424). ClinVar contains an entry for this variant (Variation ID: 6783). 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%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000007185	SCV000697855	pathogenic	Smith-Lemli-Opitz syndrome	2017-03-30	criteria provided, single submitter	clinical testing	Variant summary: The DHCR7 c.278C>T (p.Thr93Met) variant involves the alteration of a conserved nucleotide and 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome for this variant. This variant was found in 3/109422 control chromosomes from ExAC at a frequency of 0.0000274, which does not exceed the estimated maximal expected allele frequency of a pathogenic DHCR7 variant (0.0043301). Published studies have reported this variant in patients with SLOS in homozygous as well as in compound heterozygous state with other likely pathogenic/pathogenic variants. It is a known common pathogenic variant with possible founder effect in Mediterranean region. This variant is located in one of the transmembrane domains and expression of this mutant in mammalian cells showed decreased expression, lower than 5% (Witsch-Baumgartner_2000). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000007185	SCV000746859	likely pathogenic	Smith-Lemli-Opitz syndrome	2017-12-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000007185	SCV001193840	pathogenic	Smith-Lemli-Opitz syndrome	2019-12-04	criteria provided, single submitter	clinical testing	NM_001360.2(DHCR7):c.278C>T(T93M) 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 9653161, 10677299, 15670717 and 14981719. Classification of NM_001360.2(DHCR7):c.278C>T(T93M) 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.‚Äã
Revvity Omics, Revvity	RCV000007185	SCV002020374	pathogenic	Smith-Lemli-Opitz syndrome	2022-03-18	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000007185	SCV002048039	pathogenic	Smith-Lemli-Opitz syndrome	2021-09-17	criteria provided, single submitter	clinical testing	The DHCR7 c.278C>T; p.Thr93Met (rs80338853) variant has been reported in the literature in multiple individuals with Smith-Lemli-Optiz (SLO) syndrome (Fitzky 1998, Nowaczyk 2004, Witsch-Baumgartner 2000) and has been reported as a founder variant in Mediterranean populations (Nowaczyk 2004, Witsch-Baumgartner 2005). This variant is also reported in ClinVar (Variation ID: 6783) and is found in the general population with an overall allele frequency of 0.005% (14/281358 alleles) in the Genome Aggregation Database. The threonine at codon 93 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.785). Based on available information, this variant is considered pathogenic. References: Fitzky BU et al. (1998) Mutations in the Delta7-sterol reductase gene in patients with the Smith-Lemli-Opitz syndrome. Proc Natl Acad Sci U S A. 95(14):8181-6. PMID: 9653161. Nowaczyk MJ et al. (2004) Founder effect for the T93M DHCR7 mutation in Smith-Lemli-Opitz syndrome. Am J Med Genet A. 125A(2):173-6. PMID: 14981719. Witsch-Baumgartner M et al. Identification of 14 novel mutations in DHCR7 causing the Smith-Lemli-Opitz syndrome and delineation of the DHCR7 mutational spectra in Spain and Italy. Hum Mutat. 2005 Apr;25(4):412. PMID: 15776424. Witsch-Baumgartner M et al. Mutational spectrum in the Delta7-sterol reductase gene and genotype-phenotype correlation in 84 patients with Smith-Lemli-Opitz syndrome. Am J Hum Genet. 2000 Feb;66(2):402-12. PMID: 10677299.
New York Genome Center	RCV000007185	SCV002097967	pathogenic	Smith-Lemli-Opitz syndrome	2020-06-04	criteria provided, single submitter	clinical testing
Lifecell International Pvt. Ltd	RCV000007185	SCV003934932	pathogenic	Smith-Lemli-Opitz syndrome		criteria provided, single submitter	clinical testing	A Homozygote Missense variant c.278C>T in Exon 4 of the DHCR7 gene that results in the amino acid substitution p.Thr93Met was identified. The observed variant has a minimum allele frequency of 0.00004/0.00013% 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, 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. The variant has been reported to ClinVar as Pathogenic with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 6783 as of 2022-12-11). The variant has been previously recorded to cause Smith-Lemli-Opitz syndrome. This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 93 of the DHCR7 protein (p.Thr93Met) (Witsch-Baumgartner, M et al., 2000; Fitzky, B U et al., 1998). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.
Institute of Human Genetics, University Hospital Muenster	RCV003985253	SCV004801707	pathogenic	See cases	2023-10-17	criteria provided, single submitter	clinical testing	ACMG categories: PS1,PS3,PM2,PM3
OMIM	RCV000007185	SCV000027381	pathogenic	Smith-Lemli-Opitz syndrome	2012-06-01	no assertion criteria provided	literature only
GeneReviews	RCV000007185	SCV000040849	not provided	Smith-Lemli-Opitz syndrome		no assertion provided	literature only
Biochemistry Laboratory of CDMU, Chengde Medical University	RCV000007185	SCV000899186	pathogenic	Smith-Lemli-Opitz syndrome		no assertion criteria provided	case-control
Natera, Inc.	RCV000007185	SCV002093066	pathogenic	Smith-Lemli-Opitz syndrome	2017-03-17	no assertion criteria provided	clinical testing