11-71437868-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 24 ACMG points: 24P and 0B. PS1_Very_StrongPM1PM5PP3_StrongPP5_Very_Strong

The NM_001360.3(DHCR7):c.907G>A(p.Gly303Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000107 in 1,613,896 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G303W) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

DHCR7
NM_001360.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.89

Publications

13 publications found

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 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)

DHCR7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 24 ACMG points.

PS1

Transcript NM_001360.3 (DHCR7) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

PM1

In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001360.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-71437868-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 640944.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.962

PP5

Variant 11-71437868-C-T is Pathogenic according to our data. Variant chr11-71437868-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 198773.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHCR7	NM_001360.3 link	c.907G>A	p.Gly303Arg	missense_variant	Exon 8 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.907G>A	p.Gly303Arg	missense_variant	Exon 8 of 9	1	NM_001360.3	ENSP00000347717.4		Q9UBM7
DHCR7	ENST00000685320.1 link	c.322G>A	p.Gly108Arg	missense_variant	Exon 7 of 8			ENSP00000509319.1		B4E1K5

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000772

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000915

AC:

AN:

251326

AF XY:

0.0000736

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000544

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000105

AC:

153

AN:

1461740

Hom.:

Cov.:

AF XY:

0.000106

AC XY:

AN XY:

727164

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00181

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53280

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000558

AC:

AN:

1112000

Other (OTH)

AF:

0.0000993

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000125

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.000314

AC:

AN:

41424

American (AMR)

AF:

0.0000654

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000772

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000836

Hom.:

Bravo

AF:

0.000136

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000682

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000741

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Smith-Lemli-Opitz syndrome

Pathogenic:8Uncertain:1

Oct 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 303 of the DHCR7 protein (p.Gly303Arg). This variant is present in population databases (rs142808899, gnomAD 0.05%). This missense change has been observed in individual(s) with DHCR7-related conditions (PMID: 16044199, 20052364, 28503313). 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: 198773). 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%. For these reasons, this variant has been classified as Pathogenic. -

Dec 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The DHCR7 c.907G>A (p.Gly303Arg) missense variant has been reported in five studies in which it is found in a compound heterozygous state in six individuals with Smith-Lemli-Opitz syndrome (Matsumoto et al. 2005; Ko et al. 2010; Lee et al. 2010; Oh et al. 2014; Tamura et al. 2017). Five of the individuals inherited the variant from one of their unaffected carrier parents; the genotype of the sixth individual's parents is not available. The p.Gly303Arg variant was absent from 184 control chromosomes and is reported at a frequency of 0.00068 in the African American population of the Exome Sequencing Project. The p.Gly303Arg variant is located within the seventh transmembrane domain, which is a highly conserved sterol-sensing domain. Based on the evidence, the p.Gly303Arg 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. -

Jun 30, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 16, 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.907G>A (p.Gly303Arg) results in a non-conservative amino acid change located in the seventh transmembrane domain, which represent a highly conserved sterol-sensing domain (Ko_2010, Tamura_2017) 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 9.1e-05 in 251694 control chromosomes (gnomAD and publication data). This frequency is not significantly higher than expected for a pathogenic variant in DHCR7 causing Smith-Lemli-Opitz Syndrome (9.1e-05 vs 0.0043), allowing no conclusion about variant significance. c.907G>A has been reported in the literature in multiple individuals affected with Smith-Lemli-Opitz Syndrome, Autism spectrum disorder and rare neurodevelopmental disorders (Matsumoto_2005, Ko_2010, Saskin_2017, Tamura_2017, Gao_2019). 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. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1), likely pathogenic (n=2) and pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. -

Feb 25, 2016

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Biochemistry Laboratory of CDMU, Chengde Medical University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:case-control

- -

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:reference population

- -

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 10, 2022

DASA

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.907G>A;p.(Gly303Arg) missense change has been observed in affected individual(s)(PMID: 28503313; 20052364; 16044199; DOI:10.5734/JGM.2014.11.2.86) - PS4. The variant is present at low allele frequencies population databases (rs142808899– gnomAD 0.001249%; ABraOM 0.001281 frequency - http://abraom.ib.usp.br/) -PM2_supporting. The p.(Gly303Arg) was detected in trans with a Pathogenic variant (PMID: 28503313; 20052364; 16044199; DOI:10.5734/JGM.2014.11.2.86) - PM3_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is Pathogenic -

not provided

Pathogenic:2

Oct 13, 2017

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 14, 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; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 16906538, 27401223, 31178897, 28250423, 29300326, 23042628, 33179238, 33836803, 20052364, 15521979, 28503313, 16044199) -

Inborn genetic diseases

Pathogenic:1

Jul 09, 2017

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.G303R pathogenic mutation (also known as c.907G>A), located in coding exon 6 of the DHCR7 gene, results from a G to A substitution at nucleotide position 907. The glycine at codon 303 is replaced by arginine, an amino acid with dissimilar properties. This alteration was first confirmed in trans with a recurrent pathogenic alteration in two unrelated individuals of Japanese descent meeting biochemical diagnostic criteria for SLOS (Matsumoto Y et al. J. Hum. Genet., 2005 Jul;50:353-6) and has also been described in trans with other missense alterations in unrelated Japanese and Korean individuals (Tamura M et al. Hum Genome Var, 2017 May;4:17015; Ko JS et al. J. Korean Med. Sci., 2010 Jan;25:159-62). This alteration is located on the alpha helical domain and results in marked domain disruption (Li X et al. Nature, 2015 Jan;517:104-7; Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

See cases

Pathogenic:1

Feb 14, 2020

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PS4, PM2, PM3, PP3 -

DHCR7-related disorder

Pathogenic:1

Sep 12, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The DHCR7 c.907G>A variant is predicted to result in the amino acid substitution p.Gly303Arg. This variant has been reported in the compound heterozygous state in individuals with Smith-Lemli-Opitz syndrome (Matsumoto et al. 2005. PubMed ID: 16044199; Ko et al. 2010. PubMed ID: 20052364; Tamura et al. 2017. PubMed ID: 28503313). This variant is reported in 0.050% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

D;D;D;D

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.98

.;D;D;D

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.96

D;D;D;D

MetaSVM

Uncertain

0.47

MutationAssessor

Pathogenic

4.3

H;H;.;.

PhyloP100

6.9

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-7.6

D;D;D;D

REVEL

Pathogenic

0.99

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;D;.;.

Vest4

1.0

MutPred

0.95

Loss of catalytic residue at H299 (P = 0.2316);Loss of catalytic residue at H299 (P = 0.2316);.;.;

MVP

0.98

MPC

0.62

ClinPred

1.0

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.97

gMVP

1.0

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.39

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.39

Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over