rs80338860

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_001360.3(DHCR7):c.1054C>T(p.Arg352Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000018 in 1,611,952 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R352Q) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 35)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

DHCR7
NM_001360.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12U:1O:1

Conservation

PhyloP100: 3.92

Publications

24 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 18 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain 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 chr11-71435748-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 6795.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.979

PP5

Variant 11-71435749-G-A is Pathogenic according to our data. Variant chr11-71435749-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 6787.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.1054C>T	p.Arg352Trp	missense_variant	Exon 9 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.1054C>T	p.Arg352Trp	missense_variant	Exon 9 of 9	1	NM_001360.3	ENSP00000347717.4		Q9UBM7
DHCR7	ENST00000685320.1 link	c.469C>T	p.Arg157Trp	missense_variant	Exon 8 of 8			ENSP00000509319.1		B4E1K5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

248974

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000179

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1459710

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

725960

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33452

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39652

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52376

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000198

AC:

AN:

1111074

Other (OTH)

AF:

0.0000332

AC:

AN:

60324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

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:

0.00000657

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68048

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000234

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12Uncertain:1Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Smith-Lemli-Opitz syndrome

Pathogenic:7Other:1

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2015

Counsyl

Significance: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. -

Mar 17, 2017

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2001

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Dec 10, 2018

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.1054C>T (p.Arg352Trp) results in a non-conservative amino acid change in 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 1.8e-05 in 275158 control chromosomes (gnomAD). The variant, c.1054C>T, has been reported in the literature in multiple individuals affected with Smith-Lemli-Opitz Syndrome (Fitzky_1998, Witsch-Baumgartner_2001, Waterham_2012). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence showing more than 90% reduction in protein expression associated with this variant (Fitzky_1998). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Oct 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 tryptophan, which is neutral and slightly polar, at codon 352 of the DHCR7 protein (p.Arg352Trp). This variant is present in population databases (rs80338860, gnomAD 0.004%). This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 9653161, 15521979, 18006960; internal data). 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: 6787). 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: 9653161). This variant disrupts the p.Arg352 amino acid residue in DHCR7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16044199, 17441222, 21696385). 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. -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

not provided

Pathogenic:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 30, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Expression studies found that this variant is associated with significantly decreased DHCR7 protein expression (Fitzky BU et al., 1998); Not observed at a significant frequency in large population cohorts (gnomAD); 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: 10602371, 15952211, 16207203, 18006960, 16983147, 21696385, 17441222, 16044199, 20301322, 31840946, 22975760, 11175299, 15521979, 9653161, 25040602, 23042628) -

Jan 19, 2017

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

DHCR7-related disorder

Pathogenic:1

Sep 17, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The DHCR7 c.1054C>T variant is predicted to result in the amino acid substitution p.Arg352Trp. This variant has been reported alone or with a second DHCR7 variant in individuals with Smith-Lemli-Opitz syndrome (see for example, Fitzky et al 1998. PubMed ID: 9653161; Witsch-Baumgartner et al 2001. PubMed ID: 11175299; Pappu et al 2006. PubMed ID: 16983147). In vitro experimental studies suggest this variant impacts protein function (Fitzky et al 1998. PubMed ID: 9653161). Alternative nucleotide changes affecting the same amino acid (p.Arg352Gln, p.Arg352Leu) have also been reported in individuals with Smith-Lemli-Opitz syndrome (Witsch-Baumgartner et al. 2000. PubMed ID: 10677299; Al-Owain et al. 2012. PubMed ID: 21696385). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic. -

Microcephaly

Uncertain:1

Department of Pediatrics, Samsung Medical Center, Samsung Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

D;D;D

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.81

LIST_S2

Pathogenic

0.99

.;D;D

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.2

H;H;.

PhyloP100

3.9

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-7.6

D;D;D

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.045

D;D;T

Polyphen

1.0

D;D;.

Vest4

0.98

MVP

0.97

MPC

0.55

ClinPred

1.0

GERP RS

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

3.5

Varity_R

0.93

gMVP

0.97

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over