rs80338856

Variant names:

• chr11-71438986-G-A
• rs80338856
• NM_001360.3:c.724C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_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. 13/22 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. R242P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00020 (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: 5.41
• Publications: 27 publications found

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 Gene-Disease associations (from GenCC):

• Smith-Lemli-Opitz syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Myriad Women’s Health, Laboratory for Molecular Medicine, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001360.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-71438985-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2036105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 21275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001360.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHCR7	NM_001360.3	MANE Select	c.724C>T	p.Arg242Cys	missense	Exon 7 of 9	NP_001351.2
	DHCR7	NM_001425107.1		c.775C>T	p.Arg259Cys	missense	Exon 8 of 10	NP_001412036.1
	DHCR7	NM_001425108.1		c.760C>T	p.Arg254Cys	missense	Exon 7 of 9	NP_001412037.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHCR7	ENST00000355527.8	TSL:1 MANE Select	c.724C>T	p.Arg242Cys	missense	Exon 7 of 9	ENSP00000347717.4
	DHCR7	ENST00000407721.6	TSL:1	c.724C>T	p.Arg242Cys	missense	Exon 7 of 9	ENSP00000384739.2
	DHCR7	ENST00000685320.1		c.139C>T	p.Arg47Cys	missense	Exon 6 of 8	ENSP00000509319.1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152234 Hom.: 0 Cov.: 34

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

GnomAD2 exomes AF: 0.0000995 AC: 25 AN: 251340 AF XY: 0.000110

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 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.: 0 Cov.: 33 AF XY: 0.000198 AC XY: 144 AN XY: 727154

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53288

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000237 AC: 264 AN: 1112002

Other (OTH) AF: 0.000282 AC: 17 AN: 60390

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152234 Hom.: 0 Cov.: 34 AF XY: 0.000148 AC XY: 11 AN XY: 74372

African (AFR) AF: 0.000121 AC: 5 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68048

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000206 Hom.: 0

Bravo AF: 0.000162

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000824 AC: 10

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

Sep 06, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 04, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

Dec 04, 2019

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Mar 06, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Dec 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Sep 11, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

May 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The DHCR7 c.724C>T; p.Arg242Cys variant (rs80338856; ClinVar ID: 21275) is reported in the literature in multiple individuals affected with Smith-Lemli-Opitz syndrome, many of whom carry an additional pathogenic DHCR7 variant (Boland 2016, Correa-Cerro 2005, Ginat 2004, Neklason 1999, Tucci 2016, Waye 2005). This variant is found in the general population with an overall allele frequency of 0.01% (27/282,746 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is deleterious (REVEL: 0.951). The p.Arg242Cys variant occurs in transmembrane domain 5 where multiple other pathogenic variants occur (Correa-Cerro 2005), and patient cells with the p.Arg242Cys variant exhibit reduced enzymatic activity (Ginat 2004, Neklason 1999). Based on available information, this variant is considered to be pathogenic. References: Boland MR and Tatonetti NP. Investigation of 7-dehydrocholesterol reductase pathway to elucidate off-target prenatal effects of pharmaceuticals: a systematic review. Pharmacogenomics J. 2016 Oct;16(5):411-29. PMID: 27401223. Correa-Cerro LS and Porter FD. 3beta-hydroxysterol Delta7-reductase and the Smith-Lemli-Opitz syndrome. Mol Genet Metab. 2005 Feb;84(2):112-26. PMID: 15670717. Ginat S et al. Lowered DHCR7 activity measured by ergosterol conversion in multiple cell types in Smith-Lemli-Opitz syndrome. Mol Genet Metab. 2004 Sep-Oct;83(1-2):175-83. PMID: 15464432. Neklason DW et al. Biochemical variants of Smith-Lemli-Opitz syndrome. Am J Med Genet. 1999 Aug 27;85(5):517-23. PMID: 10405455. Tucci A et al. The p.Phe174Ser mutation is associated with mild forms of Smith Lemli Opitz Syndrome. BMC Med Genet. 2016 Mar 11;17:22. PMID: 26969503. Waye JS et al. Identification of nine novel DHCR7 missense mutations in patients with Smith-Lemli-Opitz syndrome (SLOS). Hum Mutat. 2005 Jul;26(1):59. PMID: 15954111.

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:2

Sep 08, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 05, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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)

Inborn genetic diseases Pathogenic:1

Aug 19, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 17, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		5.4
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.6	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MVP		0.97
MPC		0.66
ClinPred		0.99	D
GERP RS		4.4
PromoterAI		-0.0014	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.85
gMVP		0.99
Mutation Taster		=3/97	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs80338856; hg19: chr11-71150032; COSMIC: COSV62794510; COSMIC: COSV62794510;