11-71437913-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_001360.3(DHCR7):c.862G>A(p.Glu288Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000285 in 1,613,806 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

DHCR7
NM_001360.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:3

Conservation

PhyloP100: 6.89

Publications

6 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: Likely_pathogenic. The variant received 9 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001360.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.972

PP5

Variant 11-71437913-C-T is Pathogenic according to our data. Variant chr11-71437913-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500764. Variant chr11-71437913-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500764. Variant chr11-71437913-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500764. Variant chr11-71437913-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500764. Variant chr11-71437913-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500764. Variant chr11-71437913-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500764. Variant chr11-71437913-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500764. Variant chr11-71437913-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500764. Variant chr11-71437913-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500764. Variant chr11-71437913-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500764. Variant chr11-71437913-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500764. Variant chr11-71437913-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500764. Variant chr11-71437913-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500764. Variant chr11-71437913-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500764. Variant chr11-71437913-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500764. Variant chr11-71437913-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500764. Variant chr11-71437913-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500764. Variant chr11-71437913-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500764. Variant chr11-71437913-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500764. Variant chr11-71437913-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500764. Variant chr11-71437913-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500764. Variant chr11-71437913-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500764. Variant chr11-71437913-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500764. Variant chr11-71437913-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500764. Variant chr11-71437913-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500764. Variant chr11-71437913-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500764. Variant chr11-71437913-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500764. Variant chr11-71437913-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500764. Variant chr11-71437913-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500764. Variant chr11-71437913-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500764. Variant chr11-71437913-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500764. Variant chr11-71437913-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500764. Variant chr11-71437913-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500764. Variant chr11-71437913-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500764. Variant chr11-71437913-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500764. Variant chr11-71437913-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500764. Variant chr11-71437913-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500764. Variant chr11-71437913-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500764. Variant chr11-71437913-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500764. Variant chr11-71437913-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500764. Variant chr11-71437913-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500764. Variant chr11-71437913-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500764. Variant chr11-71437913-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500764. Variant chr11-71437913-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500764. Variant chr11-71437913-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 500764.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHCR7	NM_001360.3 link	c.862G>A	p.Glu288Lys	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.862G>A	p.Glu288Lys	missense_variant	Exon 8 of 9	1	NM_001360.3	ENSP00000347717.4		Q9UBM7
DHCR7	ENST00000685320.1 link	c.277G>A	p.Glu93Lys	missense_variant	Exon 7 of 8			ENSP00000509319.1		B4E1K5

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152192

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

251000

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000281

AC:

AN:

1461496

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727054

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33478

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53064

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000315

AC:

AN:

1111984

Other (OTH)

AF:

0.0000331

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

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:

0.0000328

AC:

AN:

152310

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41572

American (AMR)

AF:

0.0000653

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

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:

0.0000434

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Smith-Lemli-Opitz syndrome

Pathogenic:5Uncertain:1

May 08, 2023

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: DHCR7 c.862G>A (p.Glu288Lys) results in a conservative amino acid change located in the Transmembrane region (Peng_2018) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. A recent study using computational investigation to model the effect on protein and make predictions on SLOS phenotype based on structural and conservation properties reported this variant among Pathogenic alterations in the DHCR7 gene based on lower Relative solvent accesible surface area (rSASA), and higher evolutionary conservation (EC) compared with non-pathogenic variants (example, Peng_2018). This supports the notion of a critical amino acid residue essential for protein function. The variant allele was found at a frequency of 1.6e-05 in 251000 control chromosomes. c.862G>A has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with Smith-Lemli-Opitz Syndrome while an earlier mutational update lists this variant among mutations in patients with Smith-Lemli-Opitz Syndrome without specifying a genotype/zygosity (example, Romano_2005, Witsch-Baumgartner_2001). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29300326, 16392899, 11241839). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (LP, n=2; VUS, n=4). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Jun 17, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 10, 2019

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Apr 20, 2018

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. -

Dec 01, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 288 of the DHCR7 protein (p.Glu288Lys). This variant is present in population databases (rs565893436, gnomAD 0.006%). This missense change has been observed in individual(s) with Smith‚ÄìLemli‚ÄìOpitz syndrome (PMID: 16392899). ClinVar contains an entry for this variant (Variation ID: 500764). 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%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

DHCR7-related disorder

Pathogenic:1

Sep 17, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The DHCR7 c.862G>A variant is predicted to result in the amino acid substitution p.Glu288Lys. This variant has been reported in a cohort of individuals with Smith-Lemli-Opitz syndrome, though no additional information was provided on variant zygosity or patient genotype (Witsch-Baumgartner et al. 2001. PubMed ID: 11241839). It was also reported in the compound heterozygous state with a second DHCR7 variant (p.Ile251Asn) in an individual with Smith-Lemli Opitz syndrome (Romano et al. 2005. PubMed ID: 16392899). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as likely pathogenic. -

Inborn genetic diseases

Uncertain:1

Jun 01, 2020

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The alteration results in an amino acid change:_x000D_ _x000D_ The c.862G>A (p.E288K) alteration is located in exon 8 (coding exon 6) of the DHCR7 gene. This alteration results from a G to A substitution at nucleotide position 862, causing the glutamic acid (E) at amino acid position 288 to be replaced by a lysine (K). The alteration is rare in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the c.862G>A alteration was observed in 0.0016% (4/25100) of total alleles studied. The alteration has been observed in affected individuals:_x000D_ _x000D_ This alteration has been described from a cohort of individuals with SLOS, as well as occurring in trans with a second missense variant in one individual with a severe phenotype (Romano, 2005; Witsch-Baumgartner, 2001). The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.E288 amino acid is conserved in available vertebrate species. The amino acid is located in a structurally important protein domain:_x000D_ _x000D_ The p.E288K amino acid is located in the transmembrane domain 6 (TM6) and causes changes in protein dynamics which might lead to protein dysfunction (Peng 2018). The alteration is predicted deleterious by in silico modeling:_x000D_ _x000D_ The p.E288K alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Mar 07, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

D;D;D;D;.

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

0.98

.;D;D;D;D

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.97

D;D;D;D;D

MetaSVM

Uncertain

0.19

MutationAssessor

Pathogenic

4.3

H;H;.;.;.

PhyloP100

6.9

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-3.7

D;D;D;D;D

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;.

Polyphen

1.0

D;D;.;.;.

Vest4

1.0

MutPred

0.92

Gain of methylation at E288 (P = 0.0115);Gain of methylation at E288 (P = 0.0115);.;.;.;

MVP

0.99

MPC

0.61

ClinPred

1.0

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.96

gMVP

1.0

Mutation Taster

=6/94

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over