11-71441392-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_001360.3(DHCR7):c.461C>G(p.Thr154Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000336 in 1,613,950 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. T154M) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00036 ( 0 hom. )

Consequence

DHCR7
NM_001360.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16

Conservation

PhyloP100: 6.92

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 18 ACMG points.

PM1

In a transmembrane_region Helical (size 20) in uniprot entity DHCR7_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_001360.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-71441392-G-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.965

PP5

Variant 11-71441392-G-C is Pathogenic according to our data. Variant chr11-71441392-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 166988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-71441392-G-C is described in Lovd as [Pathogenic]. Variant chr11-71441392-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHCR7	NM_001360.3 link	c.461C>G	p.Thr154Arg	missense_variant	Exon 6 of 9	ENST00000355527.8	NP_001351.2	Q9UBM7A0A024R5F7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHCR7	ENST00000355527.8 link	c.461C>G	p.Thr154Arg	missense_variant	Exon 6 of 9	1	NM_001360.3	ENSP00000347717.4		Q9UBM7
DHCR7	ENST00000685320.1 link	c.-125C>G		5_prime_UTR_variant	Exon 5 of 8			ENSP00000509319.1		B4E1K5

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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:

0.0000961

AC:

AN:

249850

Hom.:

AF XY:

0.0000961

AC XY:

AN XY:

135238

show subpopulations

Gnomad AFR exome

AF:

0.000123

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:

0.00

Gnomad NFE exome

AF:

0.000187

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000358

AC:

524

AN:

1461718

Hom.:

Cov.:

AF XY:

0.000329

AC XY:

239

AN XY:

727164

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000458

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000125

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.0000482

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:

0.000238

Hom.:

Bravo

AF:

0.000125

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Smith-Lemli-Opitz syndrome

Pathogenic:12

Oct 12, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 24, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 19, 2024

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM1, PM2, PM3_Strong, PM5, PP3 -

Oct 09, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Smith-Lemli-Opitz syndrome (MIM#270400). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Exceptionally mild and severe cases have been reported, with intra and interfamilial variable expressivity (PMIDs: 35305950, 20301322). (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to arginine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (25 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2) (highest allele count: 1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated ERG4_ERG24 domain (DECIPHER). (I) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. An alternative change to methionine has been classified as pathogenic by multiple laboratories in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with Smith-Lemli-Opitz syndrome (ClinVar, PMIDs: 11175299, 15952211, 15805162). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_001360.2:c.1342G>A; p.(Glu448Lys)) in a recessive disease. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Apr 27, 2016

Division of Human Genetics, Children's Hospital of Philadelphia

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jun 24, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 154 of the DHCR7 protein (p.Thr154Arg). This variant is present in population databases (rs143312232, gnomAD 0.02%). This missense change has been observed in individual(s) with DHCR7-related conditions (PMID: 15805162, 15952211, 17237122, 20694756). 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: 166988). 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%. This variant disrupts the p.Thr154 amino acid residue in DHCR7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10677299, 10995508, 11427181, 15896653, 18249054, 22391996). 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. -

Mar 26, 2021

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: DHCR7 c.461C>G (p.Thr154Arg) results in a non-conservative amino acid change located in the membrane-associated helix (MAH 3, Waterham_2012) 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 4e-05 in 774648 control chromosomes (gnomAD and publication data). This frequency is not higher than expected for a pathogenic variant in DHCR7 causing Smith-Lemli-Opitz Syndrome (4e-05 vs 0.0043), allowing no conclusion about variant significance. c.461C>G has been reported in the literature in multiple individuals affected with Smith-Lemli-Opitz Syndrome (Witsch-Baumgartner_2001, Correa-Cerro__2005, Scalco_2005, Haas_2007, Boland_2016). These data indicate that the variant is very likely to be associated with disease. Additionally, another variant at the same residue T154M has been observed in affected SLOS individuals (Witsch-Baumgartner_2001, Correa-Cerro__2005, Boland_2016), suggesting that the variant is clinically significant. 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 (n=2) and likely pathogenic (n=4). Based on the evidence outlined above, the variant was classified as pathogenic. -

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 21, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 21, 2021

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 16, 2018

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The DHCR7 c.461C>G (p.Thr154Arg) missense variant has been reported in at least four studies in which it is found in a total of four patients with either diagnosed or suspected Smith-Lemli-Opitz syndrome. The variant was present in three patients in a compound heterozygous state and in one patient in a heterozygous state, in whom it is not clear if a second variant was present (Witsch-Baumgartner et al. 2001; Correa-Cerro et al. 2005; Scalco et al. 2005; Haas et al. 2007). The p.Thr154Arg variant was also identified in a heterozygous state in six unaffected individuals in a large cohort undergoing routine carrier screening using next generation sequencing (Lazarin et al. 2017). Control data are unavailable for this variant, which is reported at a frequency of 0.00035 in the European American population of the Exome Sequencing Project. Based on the evidence, the p.Thr154Arg variant is classified as likely 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

Pathogenic:2

Jan 12, 2017

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 05, 2022

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: 20694756, 10995508, 10677299, 29300326, 28166604, 23042628, 15805162, 11175299, 11241839, 15670717, 12914579, 17237122, 15952211, 34426522) -

Inborn genetic diseases

Pathogenic:1

Jul 13, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.461C>G (p.T154R) alteration is located in exon 6 (coding exon 4) of the DHCR7 gene. This alteration results from a C to G substitution at nucleotide position 461, causing the threonine (T) at amino acid position 154 to be replaced by an arginine (R). Based on data from the Genome Aggregation Database (gnomAD) database, the DHCR7 c.461C>G alteration was observed in 0.01% (25/281248) of total alleles studied, with a frequency of 0.02% (22/127708) in the European (non-Finnish) subpopulation. This mutation has been detected in four individuals with Smith-Lemli-Opitz syndrome (SLOS); three of the individuals carried another pathogenic mutation although the phase of these alterations was unknown (Witsch-Baumgartner, 2001; Correa-Cerro, 2005; Scalco, 2005; Haas, 2007). Based on our internal structural analysis, this mutation is predicted to be more destabilizing than nearby known pathogenic variants (Li, 2015). The p.T154R 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

Dec 13, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The DHCR7 c.461C>G variant is predicted to result in the amino acid substitution p.Thr154Arg. This variant has been reported in at least three patients with Smith-Lemli-Opitz syndrome (SLOS) in addition to a second known pathogenic DHCR7 variant (Correa-Cerro et al. 2005. PubMed ID: 15805162; Scalco et al. 2005. PubMed ID: 15952211; Haas et al. 2007. PubMed ID: 17237122). It has also been reported in other SLOS patient cohorts without additional genetic segregation data included about the reported patients (Witsch-Baumgartner et al. 2001. PubMed ID: 11241839; Witsch-Baumgartner et al. 2001. PubMed ID: 11175299). A different substitution of the same amino acid (p.Thr154Met) has been reported in a number of compound heterozygous SLOS patients (Wassif et al. 2005. PubMed ID: 15896653; Jezela-Stanek et al. 2008. PubMed ID: 18249054; Roullet et al. 2012. PubMed ID: 22391996) and in an expression study using HEK293 cells, the p.Thr154Met substitution was found to lead to <5% expression (Witsch-Baumgartner et al. 2000. PubMed ID: 10677299). The p.Thr154 amino acid is located in the third membrane-associated helix (MAH 3) of the DHCR7 protein (Waterham and Hennekam. 2012. PubMed ID: 23042628), and an internal summary of amino acid substitution prediction programs predicts the p.Thr154Arg change to be “damaging” (Liu et al. 2016. PMID: 26555599). This variant has been reported at a frequency of ~0.015% in individuals of European (Non-Finnish) origin in a large population database and has been interpreted in ClinVar as pathogenic/likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/166988/). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.56

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.99

D;D;.;D

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.94

.;D;D;D

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.9

H;H;.;.

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-4.8

D;D;D;D

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.0030

D;D;.;.

Polyphen

1.0

D;D;.;.

Vest4

0.97

MVP

0.96

MPC

0.60

ClinPred

0.98

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.95

gMVP

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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