rs80338853

chr11-71444036-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T93K) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000052 (0 hom.)
• Consequence: DHCR7 NM_001360.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15 O:1
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-71444036-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2968929.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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	UniProt
DHCR7	NM_001360.3	c.278C>T	p.Thr93Met	missense_variant	4/9	ENST00000355527.8
DHCR7	NM_001163817.2	c.278C>T	p.Thr93Met	missense_variant	4/9
DHCR7	XM_011544777.3	c.278C>T	p.Thr93Met	missense_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DHCR7	ENST00000355527.8	c.278C>T	p.Thr93Met	missense_variant	4/9	1	NM_001360.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152170 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000400 AC: 10 AN: 249996 Hom.: 0 AF XY: 0.0000444 AC XY: 6 AN XY: 135146

Gnomad AFR exome AF: 0.0000620

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000708

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000520 AC: 76 AN: 1461242 Hom.: 0 Cov.: 30 AF XY: 0.0000633 AC XY: 46 AN XY: 726894

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000594

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152170 Hom.: 0 Cov.: 33 AF XY: 0.0000942 AC XY: 7 AN XY: 74332

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000541 Hom.: 0

Bravo AF: 0.0000718

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Smith-Lemli-Opitz syndrome Pathogenic:11 Other:1

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	Invitae	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. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2012	- -
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, 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	Revvity Omics, Revvity	Mar 18, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
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	case-control	Biochemistry Laboratory of CDMU, Chengde Medical University	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 18, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Jun 04, 2020	- -

not provided Pathogenic:2

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) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 05, 2013	- -

Abnormal brain morphology Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

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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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D;.;D;D;D;.
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M;M;.;.;.;.;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.7	D;D;D;D;D;D;D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0050	D;D;D;D;D;D;D
Sift4G	Uncertain	0.0090	D;D;.;.;D;.;.
Polyphen		1.0	D;D;.;.;.;.;.
Vest4		0.83
MVP		0.95
MPC		0.56
ClinPred		0.83	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80338853; hg19: chr11-71155082; COSMIC: COSV62795459; COSMIC: COSV62795459;