rs80338855

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The ENST00000685320.1(DHCR7):c.-80C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,614,112 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

DHCR7
ENST00000685320.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11O:1

Conservation

PhyloP100: 8.72

Variant links:

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 links:

DHCR7 (HGNC:):

DHCR7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-71441347-G-A is Pathogenic according to our data. Variant chr11-71441347-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 21274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-71441347-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DHCR7	NM_001360.3 linkuse as main transcript	c.506C>T	p.Ser169Leu	missense_variant	6/9	ENST00000355527.8	NP_001351.2	Q9UBM7A0A024R5F7
DHCR7	NM_001163817.2 linkuse as main transcript	c.506C>T	p.Ser169Leu	missense_variant	6/9		NP_001157289.1	Q9UBM7A0A024R5F7
DHCR7	XM_011544777.3 linkuse as main transcript	c.506C>T	p.Ser169Leu	missense_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DHCR7	ENST00000685320.1 linkuse as main transcript	c.-80C>T		5_prime_UTR_premature_start_codon_gain_variant	5/8			ENSP00000509319.1	B4E1K5
DHCR7	ENST00000355527.8 linkuse as main transcript	c.506C>T	p.Ser169Leu	missense_variant	6/9	1	NM_001360.3	ENSP00000347717.4	Q9UBM7
DHCR7	ENST00000685320.1 linkuse as main transcript	c.-80C>T		5_prime_UTR_variant	5/8			ENSP00000509319.1	B4E1K5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000478

AC:

AN:

250928

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135698

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000795

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000253

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000288

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000134

Hom.:

Bravo

AF:

0.0000416

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Smith-Lemli-Opitz syndrome

Pathogenic:9Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 14, 2020	Variant summary: DHCR7 c.506C>T (p.Ser169Leu) results in a non-conservative amino acid change located in the Transmembrane domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 250928 control chromosomes. c.506C>T has been reported in the literature in multiple individuals affected with Smith-Lemli-Opitz Syndrome (example, Yu_2000, Witsch-Baumgartner_2000, Bianconi_2011, Roullet_2012, Quelin_2012, Eroglu_2017). These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect due to the compound heterozygous genotype of the cell line evaluated (Ginat_2004). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Pathogenic, n=1; Likely pathogenic, n=2; VUS, n=1). Some submitters have cited overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 03, 2020	The DHCR7 c.506C>T, p.Ser169Leu variant (rs80338855) has been reported in multiple patients diagnosed with Smith-Lemli-Opitz syndrome (Correa-Cerro 2005, Witsch-Baumgartner 2000), and found with another pathogenic variant in one individual (Yu 2000). It is listed in ClinVar (Variation ID: 21274), and is observed in the general population databases at a frequency of 0.008 percent in the Exome Variant Server (1/12988 alleles), and 0.005 percent in the Genome Aggregation Database (12/245720 alleles). Based on the high frequency of this variant in published reports of Smith-Lemli-Opitz syndrome, the p.Ser169Leu variant is classified as pathogenic. References: Correa-Cerro L et al. 3beta-hydroxysterol Delta7-reductase and the Smith-Lemli-Opitz syndrome. Mol Genet Metab. 2005; 84(2):112-26. 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; 66(2):402-12. Yu H et al. Spectrum of Delta(7)-dehydrocholesterol reductase mutations in patients with the Smith-Lemli-Opitz (RSH) syndrome. Hum Mol Genet. 2000; 9(9):1385-91. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 169 of the DHCR7 protein (p.Ser169Leu). This variant is present in population databases (rs80338855, gnomAD 0.008%). This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 10814720, 15896653, 21990131, 22226660, 22391996). ClinVar contains an entry for this variant (Variation ID: 21274). 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	clinical testing	Natera, Inc.	Mar 19, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Nov 08, 2021	The DHCR7 c.506C>T variant is a single nucleotide change in exon 6/9 of the DHCR7 gene, which is predicted to change the amino acid serine at position 169 in the protein to leucine. The variant is rare in gnomAD (1/152,224 heterozygotes, 0 homozygotes) (PM2). This variant is detected in trans with the pathogenic DHCR7:c.964-1G>C variant in this patient. The same compound heterozygous genoype has also been reported in at least two other families with a confirmed diagnosis of Smith-Lemli-Opitz syndrome (PMID: 27401223) (PM3_strong). The variant has been identified in at least 7 probands with a clinical presentation of Smith-Lemli-Opitz syndrome; this represents a significant increase in the prevalence of the variant in affected individuals compared with the prevalence in control subjects (PS4_strong). The variant has been reported as pathogenic by other diagnostic laboratories (ClinVar Variation ID: 21274) and has been reported in the HGMD database: CM001124. Computational predictions support a deleterious effect on the gene or gene product (PP3). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 09, 2019	NM_001360.2(DHCR7):c.506C>T(S169L) is classified as likely pathogenic in the context of Smith-Lemli-Opitz syndrome. Sources cited for classification include the following: PMID 15464432, 10814720, 22226660, 22391996, 21990131 and 10677299. Classification of NM_001360.2(DHCR7):c.506C>T(S169L) is based on the following criteria: This variant 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 18, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 29, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 05, 2024	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2018

The p.S169L pathogenic mutation (also known as c.506C>T), located in coding exon 4 of the DHCR7 gene, results from a C to T substitution at nucleotide position 506. The serine at codon 169 is replaced by leucine, an amino acid with dissimilar properties. This mutation has been identified in conjunction with a second DHCR7 alteration in multiple individuals with Smith-Lemli-Opitz syndrome (Witsch-Baumgartner M et al. Am. J. Hum. Genet., 2000 Feb;66:402-12; Yu H et al. Hum. Mol. Genet., 2000 May;9:1385-91; Ginat S et al. Mol. Genet. Metab., 2004;83:175-83; Bianconi SE et al. Am. J. Med. Genet. A, 2011 Nov;155A:2732-8; Roullet JB et al. J. Inherit. Metab. Dis., 2012 Sep;35:859-69). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 31, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.95

D;D;.

Eigen

Benign

0.17

Eigen_PC

Benign

0.056

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.96

.;D;D

M_CAP

Pathogenic

0.31

MetaRNN

Uncertain

0.74

D;D;D

MetaSVM

Pathogenic

0.94

MutationAssessor

Benign

1.7

L;L;.

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.5

D;D;D

REVEL

Pathogenic

0.71

Sift

Benign

0.033

D;D;D

Sift4G

Uncertain

0.030

D;D;.

Polyphen

0.99

D;D;.

Vest4

0.67

MVP

0.96

MPC

0.50

ClinPred

0.37

GERP RS

3.2

Varity_R

0.30

gMVP

0.92

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over