rs398123607

chr11-71437934-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_001360.3(DHCR7):c.841G>A(p.Val281Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000304 in 1,613,210 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. V281A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: DHCR7 NM_001360.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001360.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.903
• PP5: Variant 11-71437934-C-T is Pathogenic according to our data. Variant chr11-71437934-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 93724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-71437934-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DHCR7	NM_001360.3	c.841G>A	p.Val281Met	missense_variant	8/9	ENST00000355527.8
DHCR7	NM_001163817.2	c.841G>A	p.Val281Met	missense_variant	8/9
DHCR7	XM_011544777.3	c.841G>A	p.Val281Met	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DHCR7	ENST00000355527.8	c.841G>A	p.Val281Met	missense_variant	8/9	1	NM_001360.3	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000999 AC: 25 AN: 250306 Hom.: 0 AF XY: 0.0000813 AC XY: 11 AN XY: 135324

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000637

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000329 AC: 48 AN: 1461012 Hom.: 0 Cov.: 32 AF XY: 0.0000289 AC XY: 21 AN XY: 726806

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000693

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74348

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

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: 0.000104 Hom.: 0

Bravo AF: 0.0000718

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Smith-Lemli-Opitz syndrome Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 14, 2018	The DHCR7 c.841G>A (p.Val281Met) missense variant has been reported in a compound heterozygous state in nine individuals affected with Smith-Lemli-Opitz syndrome (SLOS) (Witsch-Baumgartner et al. 2000; Nowaczyk et al. 2004; Nowaczyk et al. 2012; Solomon et al. 2015). In eight of these individuals, the variant was identified in trans with a second missense variant, including a previously described founder variant. These individuals exhibited a mild or moderate-to-severe phenotype. The p.Val281Met variant was also found in trans with a null allele in one individual who died two days after birth and displayed syndactyly, microcephaly, and hypotonia (Solomon et al. 2015). This individual's healthy father was a heterozygous carrier of the p.Val281Met variant, while the healthy mother was heterozygous for the null allele. Control data are unavailable for this variant, which is reported at a frequency of 0.000685 in the Latino population of the Genome Aggregation Database. Based on the evidence, p.Val281Met 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 23, 2020	Variant summary: DHCR7 c.841G>A (p.Val281Met) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 250306 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in DHCR7 causing Smith-Lemli-Opitz Syndrome (0.0001 vs 0.0043), allowing no conclusion about variant significance. c.841G>A has been reported in the literature in multiple individuals affected with Smith-Lemli-Opitz Syndrome (example: Nowaczyk_2012, Witsch-Baumgartner_2000). Many of these patients had a mild phenotype. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Sep 26, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 281 of the DHCR7 protein (p.Val281Met). This variant is present in population databases (rs398123607, gnomAD 0.07%). This missense change has been observed in individual(s) with clinical features of Smith–Lemli–Opitz syndrome and elevated serum 7-dehydrocholesterol (PMID: 10677299, 14981719, 17441222, 27401223; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 93724). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 03, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 09, 2020	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 30, 2012	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 23, 2022	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: 10677299, 27401223, 14981719, 28250423, 22438180, 17441222) -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 04, 2019	DNA sequence analysis of the DHCR7 gene demonstrated a sequence change, c.841G>A, in exon 8 that results in an amino acid change, p.Val281Met. This sequence change has been reported in multiple individuals with Smith-Lemli-Opitz syndrome (Witsch-Baumgartner et al., 2000; Boland et al., 2016; Nowalczyk et al., 2004; Waye et al., 2007). This sequence change has been described in the gnomaD database with a low population frequency of 0.01% (dbSNP rs398123607). The p.Val281Met change affects a highly conserved amino acid residue located in a domain of the DHCR7 protein that is known to be functional. The p.Val281Met substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, CADD, REVEL). -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 27, 2017

The p.V281M pathogenic mutation (also known as c.841G>A), located in coding exon 6 of the DHCR7 gene, results from a G to A substitution at nucleotide position 841. The valine at codon 281 is replaced by methionine, an amino acid with highly similar properties. In vitro studies have shown this mutation results in protein expression and levels less than 10% of wild-type (Witsch-Baumgartner M et al. Am. J. Hum. Genet., 2000 Feb;66:402-12). This mutation has been reported in a patient with a diagnosis of Smith-Lemli-Opitz syndrome, as determined by clinical and biochemical findings, including decreased cholesterol and elevated levels of 7-dehydrocholesterol (Nowaczyk MJ et al. Am. J. Med. Genet. A, 2004 Mar;125A:173-6). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

DHCR7-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 01, 2023

The DHCR7 c.841G>A variant is predicted to result in the amino acid substitution p.Val281Met. This variant has been reported in the compound heterozygous state in many individuals with autosomal recessive Smith-Lemli-Opitz syndrome (Witsch-Baumgartner et al. 2000. PubMed ID: 10677299; Waye et al. 2007. PubMed ID: 17441222; Nowaczyk et al. 2012. PubMed ID: 22438180). This variant was also reported in a patient from an autism cohort (Table S2 in Saskin et al 2017. PubMed ID: 28250423). This variant is reported in 0.064% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;D;D;D;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H;H;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.7	D;D;D;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.049	D;D;T;D;.
Polyphen		1.0	D;D;.;.;.
Vest4		0.97
MutPred		0.79		Loss of catalytic residue at V281 (P = 0.0018);Loss of catalytic residue at V281 (P = 0.0018);.;.;.;
MVP		0.99
MPC		0.55
ClinPred		0.91	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.82
gMVP		0.93

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: rs398123607; hg19: chr11-71148980; COSMIC: COSV105914295; COSMIC: COSV105914295;