rs80338853
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001360.3(DHCR7):c.278C>T(p.Thr93Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000558 in 1,613,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000052 ( 0 hom. )
Consequence
DHCR7
NM_001360.3 missense
NM_001360.3 missense
Scores
8
7
4
Clinical Significance
Conservation
PhyloP100: 2.93
Genes affected
DHCR7 (HGNC:2860): (7-dehydrocholesterol reductase) This gene encodes an enzyme that removes the C(7-8) double bond in the B ring of sterols and catalyzes the conversion of 7-dehydrocholesterol to cholesterol. This gene is ubiquitously expressed and its transmembrane protein localizes to the endoplasmic reticulum membrane and nuclear outer membrane. Mutations in this gene cause Smith-Lemli-Opitz syndrome (SLOS); a syndrome that is metabolically characterized by reduced serum cholesterol levels and elevated serum 7-dehydrocholesterol levels and phenotypically characterized by cognitive disability, facial dysmorphism, syndactyly of second and third toes, and holoprosencephaly in severe cases to minimal physical abnormalities and near-normal intelligence in mild cases. Alternative splicing results in multiple transcript variants that encode the same protein.[provided by RefSeq, Aug 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.945
PP5
Variant 11-71444036-G-A is Pathogenic according to our data. Variant chr11-71444036-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-71444036-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| DHCR7 | NM_001360.3 | c.278C>T | p.Thr93Met | missense_variant | 4/9 | ENST00000355527.8 | NP_001351.2 | |
| DHCR7 | NM_001163817.2 | c.278C>T | p.Thr93Met | missense_variant | 4/9 | NP_001157289.1 | ||
| DHCR7 | XM_011544777.3 | c.278C>T | p.Thr93Met | missense_variant | 4/9 | XP_011543079.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| DHCR7 | ENST00000355527.8 | c.278C>T | p.Thr93Met | missense_variant | 4/9 | 1 | NM_001360.3 | ENSP00000347717 | P1 |
Frequencies
GnomAD3 genomes 0.0000920 AC: 14AN: 152170Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000400 AC: 10AN: 249996Hom.: 0 AF XY: 0.0000444 AC XY: 6AN XY: 135146
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GnomAD4 exome AF: 0.0000520 AC: 76AN: 1461242Hom.: 0 Cov.: 30 AF XY: 0.0000633 AC XY: 46AN XY: 726894
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GnomAD4 genome 0.0000920 AC: 14AN: 152170Hom.: 0 Cov.: 33 AF XY: 0.0000942 AC XY: 7AN XY: 74332
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:15Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Smith-Lemli-Opitz syndrome Pathogenic:11Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 17, 2021 | 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. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2012 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 04, 2019 | 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 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Lifecell International Pvt. Ltd | - | 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. - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 17, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 30, 2017 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Jun 04, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 18, 2022 | - - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, no assertion criteria provided | case-control | Biochemistry Laboratory of CDMU, Chengde Medical University | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 04, 2024 | 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. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Dec 18, 2017 | - - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 05, 2013 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 01, 2021 | 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) - |
Abnormal brain morphology Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | research | Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | - | - - |
See cases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital Muenster | Oct 17, 2023 | ACMG categories: PS1,PS3,PM2,PM3 - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;.;D;D;D;.
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;M;.;.;.;.;.
MutationTaster
Benign
A;A
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D;D;D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D;D;D
Sift4G
Uncertain
D;D;.;.;D;.;.
Polyphen
D;D;.;.;.;.;.
Vest4
MVP
MPC
0.56
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at