rs398123607

Positions:

chr11-71437934-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_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 (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

DHCR7
NM_001360.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.89

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 14 ACMG points.

PM1

In a transmembrane_region Helical (size 20) in uniprot entity DHCR7_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) 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	Protein
DHCR7	NM_001360.3 linkuse as main transcript	c.841G>A	p.Val281Met	missense_variant	8/9	ENST00000355527.8	NP_001351.2
DHCR7	NM_001163817.2 linkuse as main transcript	c.841G>A	p.Val281Met	missense_variant	8/9		NP_001157289.1
DHCR7	XM_011544777.3 linkuse as main transcript	c.841G>A	p.Val281Met	missense_variant	8/9		XP_011543079.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DHCR7	ENST00000355527.8 linkuse as main transcript	c.841G>A	p.Val281Met	missense_variant	8/9	1	NM_001360.3	ENSP00000347717	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

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:

AN:

250306

Hom.:

AF XY:

0.0000813

AC XY:

AN XY:

135324

show subpopulations

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:

AN:

1461012

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

726806

show subpopulations

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:

AN:

152198

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74348

show subpopulations

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.:

Bravo

AF:

0.0000718

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Smith-Lemli-Opitz syndrome

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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‚ÄìLemli‚ÄìOpitz 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. -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Sep 26, 2018	- -
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. -
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	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 30, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 17, 2023	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, 34308104, 35460704) -

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, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 09, 2024

The DHCR7 c.841G>A variant is predicted to result in the amino acid substitution p.Val281Met. This variant has been reported to be causative for 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. 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

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

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

LIST_S2

Uncertain

0.97

.;D;D;D;D

M_CAP

Uncertain

0.29

MetaRNN

Pathogenic

0.90

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.7

H;H;.;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.72

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

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

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