rs80338856

Positions:

chr11-71438986-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_001360.3(DHCR7):c.724C>T(p.Arg242Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000191 in 1,613,974 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. R242H) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

DHCR7
NM_001360.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13O:1

Conservation

PhyloP100: 5.41

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 chr11-71438985-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.969

PP5

Variant 11-71438986-G-A is Pathogenic according to our data. Variant chr11-71438986-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 21275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-71438986-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
DHCR7	NM_001360.3 linkuse as main transcript	c.724C>T	p.Arg242Cys	missense_variant	7/9	ENST00000355527.8	NP_001351.2
DHCR7	NM_001163817.2 linkuse as main transcript	c.724C>T	p.Arg242Cys	missense_variant	7/9		NP_001157289.1
DHCR7	XM_011544777.3 linkuse as main transcript	c.724C>T	p.Arg242Cys	missense_variant	7/9		XP_011543079.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DHCR7	ENST00000355527.8 linkuse as main transcript	c.724C>T	p.Arg242Cys	missense_variant	7/9	1	NM_001360.3	ENSP00000347717	P1

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

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:

0.000250

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000995

AC:

AN:

251340

Hom.:

AF XY:

0.000110

AC XY:

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000167

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000196

AC:

287

AN:

1461740

Hom.:

Cov.:

AF XY:

0.000198

AC XY:

144

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.000237

Gnomad4 OTH exome

AF:

0.000282

GnomAD4 genome

AF:

0.000145

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.000121

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:

0.000250

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000242

Hom.:

Bravo

AF:

0.000162

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13Other: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	Illumina Laboratory Services, Illumina	Apr 27, 2017	Across a selection of available literature, the DHCR7 c.724C>T (p.Arg242Cys) missense variant has been identified in a compound heterozygous state in at least six individuals with Smith-Lemli-Opitz syndrome and in two additional patients with unknown zygosity (Neklason et al. 1999; Krakowiak et al. 2000; Witsch-Baumgartner et al. 2000; Waye et al. 2005; Tucci et al. 2016). In a review, Boland et al. (2016) report that the p.Arg242Cys variant was found in 12 out of 1037 (1.2%) patient alleles across 30 studies. The p.Arg242Cys variant was absent from 50 controls and is reported at a frequency of 0.00029 in the African population of the Exome Aggregation. Functional studies demonstrated that the enzymatic activity in fibroblasts derived from a patient who was compound heterozygous for the p.Arg242Cys variant and another missense variant was significantly reduced (Ginat et al. 2004). Based on the evidence, the p.Arg242Cys variant is classified as pathogenic for Smith-Lemli-Opitz syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 242 of the DHCR7 protein (p.Arg242Cys). This variant is present in population databases (rs80338856, gnomAD 0.02%). This missense change has been observed in individuals with Smith-Lemli-Opitz syndrome (PMID: 10405455, 10677299, 10995508, 15464432, 15954111, 26969503). ClinVar contains an entry for this variant (Variation ID: 21275). 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%. Experimental studies have shown that this missense change affects DHCR7 function (PMID: 15464432). This variant disrupts the p.Arg242 amino acid residue in DHCR7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10995508, 11427181, 12818773, 15776424, 16044199). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 06, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 04, 2019	NM_001360.2(DHCR7):c.724C>T(R242C) is classified as likely pathogenic in the context of Smith-Lemli-Opitz syndrome. Sources cited for classification include the following: PMID 10677299, 15954111, 10995508, 18076100, 10405455, and 16983147. Classification of NM_001360.2(DHCR7):c.724C>T(R242C) 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 11, 2015	The p.Arg242Cys (NM_000060.2 c.724C>T) variant in DHCR7 has been reported in at least 6 individuals with clinical features of Smith-Lemli-Opitz syndrome who wer e compound heterozygotes for a second DHCR7 variant, and segregated with disease in one affected family member (Neklason 1999, Krakowiak 2000, Waye 2002, Correa -Cerro 2005, Waye 2005, Tucci 2016). This variant has also been identified in 19 /126,670 of European chromosomes by the Genome Aggregation Database (gnomAD, htt p://gnomad.broadinstitute.org; dbSNP rs80338856). Although this variant has been seen in the general population, its frequency is low enough to be consistent wi th a recessive carrier frequency. In vitro functional studies provide some evide nce that the p.Arg242Cys variant may impact protein function (Neklason 1999). In summary, although additional studies are required to fully establish its clinic al significance, the p.Arg242Cys variant is likely pathogenic for Smith-Lemli-Op itz syndrome in an autosomal recessive manner based on its occurrence in affecte d individuals, low frequency in controls, and functional data. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 04, 2016	Variant summary: The DHCR7 c.724C>T (p.Arg242Cys) variant located in the transmembrane domain causes a missense change involving a conserved nucleotide with 5/5 in silico tools predicting a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 10/121036 (1/12106), which does not exceed the maximal expected allele frequency for a pathogenic DHCR7 variant of 1/230. The variant of interest has been reported in multiple affected individuals via publications. In addition, GeneReviews cites the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 21, 2024	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: 26969503, 22975760, 28166604, 27415407, 11175299, 10677299, 16207203, 12070263, 10405455, 10995508, 27401223, 23042628, 15464432, 15954111, 28250423, 30609409, 31589614, 34308104, 37924809) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 08, 2015	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 19, 2021

The c.724C>T (p.R242C) alteration is located in exon 7 (coding exon 5) of the DHCR7 gene. This alteration results from a C to T substitution at nucleotide position 724, causing the arginine (R) at amino acid position 242 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of 0.01% (27/282746) total alleles studied. The highest observed frequency was 0.02% (4/24962) of African alleles. This mutation was identified in multiple individuals with Smith-Lemli-Opitz syndrome (SLOS) (Neklason, 1999; Krakowiak, 2000; Ginat, 2004; Waye, 2005; Tucci, 2016; Saskin, 2017). This amino acid position is highly conserved in available vertebrate species. Enzyme activity in a cell line from an individual with SLOS with this mutation demonstrated reduced activity (Ginat, 2004). This alteration is predicted to be deleterious by in silico analysis. 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

Jun 17, 2024

The DHCR7 c.724C>T variant is predicted to result in the amino acid substitution p.Arg242Cys. This variant has been reported in multiple Smith-Lemli-Opitz syndrome (SLOS) patients (e.g., Neklason et al. 1999. PubMed ID: 10405455; Krakowiak et al. 2000. PubMed ID: 10995508; Witsch-Baumgartner et al. 2001. PubMed ID: 11175299; Tucci et al. 2016. PubMed ID: 26969503). The p.Arg242 amino acid is found in the 5th membrane-associated helix of the DHCR7 protein (Waterham and Hennekam. 2012. PubMed ID: 23042628) and the p.Arg242Cys amino acid substitution has resulted in decreased enzyme activity in experimental studies (Witsch-Baumgartner et al. 2000. PubMed ID: 10677299). In addition, a different substitution at the same location has also been reported in SLOS patients (e.g., Krakowiak et al. 2000. PubMed ID: 10995508). This variant is reported in 0.016% of alleles in individuals of African descent in gnomAD. Based on these observations, we classify the c.724C>T (p.Arg242Cys) variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

D;D;D;.

Eigen

Pathogenic

0.75

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

.;D;D;D

M_CAP

Pathogenic

0.47

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.4

M;M;.;.

MutationTaster

Benign

1.0

A;A

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-7.6

D;D;D;D

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;.

Polyphen

1.0

D;D;.;.

Vest4

0.98

MVP

0.97

MPC

0.66

ClinPred

0.99

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.85

gMVP

0.99

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