11-71441401-C-T

Position:

• chr11-71441401-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001360.3(DHCR7):​c.452G>A​(p.Trp151*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000711 in 1,613,916 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00068 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00071 (0 hom.)
• Consequence: DHCR7 NM_001360.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:32 O:2
• Conservation: PhyloP100: 6.89

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]

DHCR7 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-71441401-C-T is Pathogenic according to our data. Variant chr11-71441401-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 21273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-71441401-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DHCR7	NM_001360.3	c.452G>A	p.Trp151*	stop_gained	6/9	ENST00000355527.8	NP_001351.2
DHCR7	NM_001163817.2	c.452G>A	p.Trp151*	stop_gained	6/9		NP_001157289.1
DHCR7	XM_011544777.3	c.452G>A	p.Trp151*	stop_gained	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DHCR7	ENST00000355527.8	c.452G>A	p.Trp151*	stop_gained	6/9	1	NM_001360.3	ENSP00000347717.4
DHCR7	ENST00000685320.1	c.-134G>A		5_prime_UTR_variant	5/8			ENSP00000509319.1

Frequencies

GnomAD3 genomes AF: 0.000677 AC: 103 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00131

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000769 AC: 192 AN: 249572 Hom.: 0 AF XY: 0.000814 AC XY: 110 AN XY: 135082

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.000894

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00143

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000714 AC: 1044 AN: 1461724 Hom.: 0 Cov.: 34 AF XY: 0.000780 AC XY: 567 AN XY: 727170

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.000536

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000243

Gnomad4 NFE exome AF: 0.000872

Gnomad4 OTH exome AF: 0.000547

GnomAD4 genome AF: 0.000677 AC: 103 AN: 152192 Hom.: 0 Cov.: 33 AF XY: 0.000578 AC XY: 43 AN XY: 74350

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00131

Gnomad4 OTH AF: 0.000956

Alfa AF: 0.00136 Hom.: 0

Bravo AF: 0.000627

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000675 AC: 82

EpiCase AF: 0.00202

EpiControl AF: 0.00107

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:32 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Smith-Lemli-Opitz syndrome Pathogenic:22 Other:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 24, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 25, 2016	Variant summary: The DHCR7 c.452G>A (p.Trp151X) variant results in a premature termination codon, predicted to cause a absent DHCR7 protein due to nonsense mediated decay, which is known mechanisms for disease. This prediction has been confirmed by a study using DNA and RNA level analysis which showed that mRNA derived from blood leukocytes carrying the variant of interest lacks the p. Trp151 * allele (Balogh_MS_2012). This variant was found in 82/120858 control chromosomes at a frequency of 0.0006785, which does not exceed the estimated maximal expected allele frequency of a pathogenic DHCR7 variant (0.0043301). It was reported in several SLOS patients in either homozygosity or compound heterozygosity with other pathogenic DHCR7 alleles indicating pathogenicity. Moreover, several clinical diagnostic laboratories classify variant as pathogenic. The variant is one of the most common SLOS-causing mutations with prevalence amongst affected individuals ranging from 2.3% to 50% deepening on the population studied. Taken together, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Oct 18, 2019	The variant was confirmed as compound heterozygous with a pathogenic variant (NM_001163817.1: c.964-1G>C). -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 25, 2014	The p.Trp151X (NM_001360.2 c.452G>A) variant in DHCR7 has been reported in sever al individuals with Smith-Lemli-Opitz syndrome. Most of these individuals were c ompound heterozygous for the variant (Fitzky 1998, Correa-Cerro 2005). This vari ant has also been reported in ClinVar (Variation ID#21273), as pathogenic by mul tiple laboratories. It has been identified in 0.13% (174/125,000) of European c hromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstit ute.org; dbSNP rs11555217). Although this variant has been seen in the general p opulation, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at posi tion 151 which is predicted to lead to a truncated or absent protein. Biallelic loss of function of the DHCR7 gene is associated with Smith-Lemli-Opitz syndrome . In summary, this variant meets our criteria to be classified as pathogenic f or Smith-Lemli-Opitz syndrome in an autosomal recessive manner based on its occu rrence in individuals with this disease and a predicted null effect. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Nov 08, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	The c.452G>A (p.Trp151Ter) variant is a well-described, common stop-gained variant that accounts for 6.0% of variant DHCR7 alleles (Correa-Cerro et al. 2005a; Nowaczyk et al. 2013). Across a selection of the available literature, the p.Trp151Ter variant has been identified in at least 62 patients with Smith-Lemli-Opitz syndrome, including eight in a homozygous state and 54 in a compound heterozygous state. The p.Trp151Ter variant was also identified in a heterozygous state in 39 unaffected Polish neonates (Fitzky et al. 1998; Witsch-Baumgartner et al. 2000; Krakowiak et al. 2000; Löffler et al. 2000; Witsch-Baumgartner et al. 2001; Ciara et al. 2004; Correa-Cerro et al. 2005; Ciara et al. 2006; Kolejáková et al. 2009). The p.Trp151Ter variant was absent from 80 control individuals but is reported at a frequency of 0.00116 in the European (Non-Finnish) population of the Exome Aggregation Consortium. Functional studies demonstrated an absence of protein and no enzyme activity in HEK cells transfected with the variant (Witsch-Baumgartner et al. 2000). Correa-Cerro et al. (2005b) demonstrated that the p.Trp151Ter variant undergoes nonsense mediated decay. Haplotype analysis indicates the p.Trp151Ter variant occurs on three related haplotypes and appears to have originated in southern Poland (Witsch-Baumgartner et al. 2001; Correa-Cerro et al 2005a). Due to the potential impact of stop-gained variants and the supporting evidence from the literature, the p.Trp151Ter variant is classified as pathogenic for Smith-Lemli-Opitz syndrome. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Oct 06, 2021	PVS1, PM2, PP3, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 15, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Hadassah Hebrew University Medical Center	Jun 20, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change creates a premature translational stop signal (p.Trp151*) in the DHCR7 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DHCR7 are known to be pathogenic (PMID: 9634533, 10677299). This variant is present in population databases (rs11555217, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individuals with Smith-Lemli-Opitz syndrome (PMID: 9653161, 11078571, 11175299, 15521979, 16497572, 17965227, 19390132). ClinVar contains an entry for this variant (Variation ID: 21273). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Apr 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Mar 30, 2023	This sequence change in DHCR7 is a nonsense variant predicted to cause a premature stop codon, p.(Trp151*), in biologically-relevant-exon 6/9 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (ClinGen). The highest population minor allele frequency in gnomAD v2.1 is 0.1% (181/127,446 alleles) in the European (non-Finnish) population. This variant has been detected in at least 25 individuals with Smith-Lemli Opitz syndrome (SLOS), many with biochemical confirmation indicated by elevated 7-dehydrocholesterol. Of those individuals, two individuals were homozygous and 18 were compound heterozygous for the variant and a pathogenic variant and two of those were confirmed in trans by parental testing. The variant has been reported to segregate with SLOS in at least three families (PMID: 9653161, 11078571, 15521979). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3_VeryStrong, PP1_Strong, PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 20, 2023	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant identified in multiple participants. Variant interpreted as Pathogenic and reported, most recently, on 11-13-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 09, 2019	NM_001360.2(DHCR7):c.452G>A(W151*) is classified as pathogenic in the context of Smith-Lemli-Opitz syndrome and is associated with the severe form of the disease. Sources cited for classification include the following: PMID 9653161, 20556518, and 10677299. Classification of NM_001360.2(DHCR7):c.452G>A(W151*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	May 20, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PS3,PP4,PM3. -
Pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	May 07, 2015	The heterozygous variant in the DHCR7 gene (c.452G>A; p.Trp151Term) is considered pathogenic as this variant has been previously published in multiple affected individuals and is the third most common DHCR7 mutation (Correa-Cerro et al. 2013; PMID: 15670717; Witsch-Baumgartner et al. 200; PMID: 10677299; Löffler et al 2000, PMID: 11078571). -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Courtagen Diagnostics Laboratory, Courtagen Life Sciences	Sep 30, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Oct 23, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Oct 05, 2016	- -

not provided Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 13, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	DHCR7: PM3:Very Strong, PVS1, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 30, 2019	Reported previously in association with Smith-Lemli-Opitz syndrome (SLOS), in affected individuals who are compound heterozygous for the W151X variant and another pathogenic variant, and has been observed in the homozygous state in a lethal form of SLOS (Fitzky et al., 1998; Correa-Cerro et al., 2005b; Loffler et al., 2000); Studies of patient fibroblasts demonstrated that the transcript with this variant underwent nonsense-mediated mRNA decay in a gene for which loss-of-function is a known mechanism of disease (Correa-Cerro et al., 2005b); This variant is associated with the following publications: (PMID: 10995508, 25525159, 29300326, 27415407, 19390132, 22975760, 11175299, 16687448, 16678134, 15805162, 11078571, 27066502, 26685159, 9653161, 28166604, 29165578, 28250423, 15521979, 16497572, 20556518, 23293579, 10677299, 17965227, 29433144, 30609409, 31980526, 31589614) -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 19, 2017	- -
Pathogenic, criteria provided, single submitter	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 11, 2020

The c.452G>A (p.W151*) alteration, located in exon 6 (coding exon 4) of the DHCR7 gene, consists of a G to A substitution at nucleotide position 452. This changes the amino acid from a tryptophan (W) to a stop codon at amino acid position 151. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This recurrent mutation has been documented to account for 6.9% of mutant alleles in DHCR7 and has been reported in the homozygous state and in trans with a second DHCR7 alteration in multiple patients with Smith Lemli Opitz syndrome (SLOS) (Fitzky, 1998; Witsch-Baumgartner, 2000; Löffler, 2000; Krakowiak, 2000; Lazarin, 2017). In addition, this was the second most commonly seen mutation on carrier screens elected from 2012-2015 (Lazarin, 2013). One study found that the carrier frequency of this mutation in Ashkenazi Jewish individuals may be as high as 1/40 and 1/122 in non-Ashkenazi Jewish individuals (Shi, 2017). Based on the available evidence, this alteration is classified as pathogenic. -

DHCR7-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 03, 2024

The DHCR7 c.452G>A variant is predicted to result in premature protein termination (p.Trp151*). This variant has been reported to be causative for Smith-Lemli-Opitz syndrome (SLOS) (Fitzky et al. 1998. PubMed ID: 9653161; Witsch-Baumgartner et al. 2001. PubMed ID: 11175299; Waterham and Hennekam. 2012. PubMed ID: 23042628). It is one of the most commonly reported causative DHCR7 variants among affected individuals of European descent (Witsch-Baumgartner et al. 2001. PubMed ID: 11175299; Ciara et al. 2006. PubMed ID: 16497572; Witsch-Baumgartner et al. 2008. PubMed ID: 17965227). This variant is reported in 0.14% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in DHCR7 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Small for gestational age;C1849185:Elevated circulating 7-dehydrocholesterol concentration;C2677180:Primary microcephaly;C4551570:2-3 toe syndactyly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Dec 20, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.93	D
Vest4		0.91
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs11555217; hg19: chr11-71152447;