11-71444952-T-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong

The NM_001360.3(DHCR7):c.1A>G(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.0000198 in 1,614,024 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 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

DHCR7
NM_001360.3 start_lost

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:19

Conservation

PhyloP100: 3.67

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 20 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 8 pathogenic variants. Next in-frame start position is after 59 codons. Genomic position: 71444139. Lost 0.123 part of the original CDS.

PS1

Another start lost variant in NM_001360.3 (DHCR7) was described as [Pathogenic] in Lovd

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-71444952-T-C is Pathogenic according to our data. Variant chr11-71444952-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6794.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-71444952-T-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.1A>G	p.Met1?	start_lost	Exon 3 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.1A>G	p.Met1?	start_lost	Exon 3 of 9	1	NM_001360.3	ENSP00000347717.4		Q9UBM7
DHCR7	ENST00000685320.1 link	c.-333-891A>G		intron_variant	Intron 2 of 7			ENSP00000509319.1		B4E1K5

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00633

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251484

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1461700

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000835

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000247

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:19

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Smith-Lemli-Opitz syndrome

Pathogenic:14

Jul 30, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 20, 2017

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: The DHCR7 c.1A>G (p.Met1Val) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 3/121390 control chromosomes at a frequency of 0.0000247, which does not exceed the estimated maximal expected allele frequency of a pathogenic DHCR7 variant (0.0043301). This variant has been reported in multiple compound heterozygous SLOS patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. The variant of interest affects the translational start sight, however, Scalco_2005 indicates that translational initiation at Methionine 59 produces a functional protein. Therefore, suggesting that this would help explain the mild phenotype observed in affected individuals. Taken together, this variant is classified as likely pathogenic. -

Jul 22, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2024

Daryl Scott Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PM3, PM5 -

Dec 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the DHCR7 mRNA. The next in-frame methionine is located at codon 59. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of the initiator codon has been observed in individuals with Smith-Lemli-Opitz syndrome (PMID: 12949967, 15776424, 15952211, 16983147, 21990131). ClinVar contains an entry for this variant (Variation ID: 6794). For these reasons, this variant has been classified as Pathogenic. -

Mar 14, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2019

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 06, 2020

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 27, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 22, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 07, 2014

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 12, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The DHCR7 c.1A>G; p.Met1? variant (rs104886033) is reported in the literature in multiple individuals affected with Smith-Lemli-Opitz syndrome (SLOS) (Bianconi 2011, Pappu 2006, Scalco 2005, Witsch-Baumgartner 2005). Most affected individuals with this variant were described with mild disease and were found to carry an additional pathogenic variant in trans (Bianconi 2011, Pappu 2006, Scalco 2005, Witsch-Baumgartner 2005). The c.1A>G variant is found on only four chromosomes (4/282880 alleles) in the Genome Aggregation Database. This variant abolishes the canonical start codon, which is likely to negatively impact gene function. While a DHCR7 protein beginning at the next downstream methionine, Met59, has been demonstrated to be enzymatically active (Wassif 2005), it is unknown if this downstream methionine is used in vivo or how the activity compares to the canonical protein. Another variant affecting the canonical methionine (c.3G>A) has also been reported in individuals affected with SLOS and is considered disease-causing (Waterham 2000). Based on available information, the c.1A>G variant is considered to be pathogenic. References: Bianconi SE et al. Adrenal function in Smith-Lemli-Opitz syndrome. Am J Med Genet A. 2011 Nov;155A(11):2732-8. Pappu AS et al. Increased nonsterol isoprenoids, dolichol and ubiquinone, in the Smith-Lemli-Opitz syndrome: effects of dietary cholesterol. J Lipid Res. 2006 Dec;47(12):2789-98. Scalco FB et al. DHCR7 mutations in Brazilian Smith-Lemli-Opitz syndrome patients. Am J Med Genet A. 2005 Jul 30;136(3):278-81. Wassif CA et al. Mutations in the human sterol delta7-reductase gene at 11q12-13 cause Smith-Lemli-Opitz syndrome. Am J Hum Genet. 1998 Jul;63(1):55-62. Waterham HR and Wanders RJ. Biochemical and genetic aspects of 7-dehydrocholesterol reductase and Smith-Lemli-Opitz syndrome. Biochim Biophys Acta. 2000 Dec 15;1529(1-3):340-56. Witsch-Baumgartner M et al. Identification of 14 novel mutations in DHCR7 causing the Smith-Lemli-Opitz syndrome and delineation of the DHCR7 mutational spectra in Spain and Italy. Hum Mutat. 2005 Apr;25(4):412. -

not provided

Pathogenic:3

Mar 11, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2, PS1, PS4, PVS1 -

Aug 23, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 15776424, 31589614, 9634533, 15952211, 12949967, 16983147, 22391996, 24500076, 21990131, 37644014) -

Jan 30, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Jun 01, 2020

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The alteration results in an initiation codon change: _x000D_ _x000D_ The c.1A>G (p.M1?) alteration is located in exon 3 (coding exon 1) of the DHCR7 gene and results from an A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. Sequence variations that modify the initiation codon (ATG) are typically deleterious in nature as they are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. However, there is an in-frame methionine 59 amino acids downstream, which may act as an alternative initiation codon and result in an N-terminal truncation; however, direct evidence is unavailable and the significance of the N-terminus for this protein is not well established. The alteration is rare in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the c.1A>G alteration was observed in 0.0014% (4/282880) of total alleles studied, with a frequency of 0.0023% (3/129192) in the European (non-Finnish) subpopulation. The alteration has been observed in affected individuals:_x000D_ _x000D_ The c.1A>G (p.M1?) alteration has been reported in multiple patients with a confirmed biochemical diagnosis of SLOS along with a second disease-causing mutation. Several patients have been reported to have mild clinical symptoms despite co-occuring with a severe allele (Bianconi, 2011; Eroglu, 2017; Scalco, 2005; Witsch-Baumgartner, 2004). The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.M1 amino acid is conserved in available vertebrate species. Based on the available evidence, this alteration is classified as pathogenic. -

DHCR7-related disorder

Pathogenic:1

Jul 15, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The DHCR7 c.1A>G variant is predicted to disrupt the translation initiation site (Start loss). This variant, which is sometimes described in the literature as p.M1V, has been reported in multiple individuals with Smith-Lemli-Opitz syndrome (Witsch-Baumgartner et al. 2005. PubMed ID: 15776424; Pappu et al. 2006. PubMed ID: 16983147; Bianconi et al. 2011. PubMed ID: 21990131). This variant is reported in 0.0028% 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

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.52

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.34

T;T;.;T;T;T;T

Eigen

Benign

0.020

Eigen_PC

Benign

0.041

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.90

.;D;D;D;D;D;D

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.84

D;D;D;D;D;D;D

MetaSVM

Uncertain

0.75

PROVEAN

Benign

-0.54

N;N;N;N;N;N;N

REVEL

Pathogenic

0.66

Sift

Pathogenic

0.0

D;D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;.;.;D;.;D

Polyphen

0.66

P;P;.;.;.;.;.

Vest4

0.98

MutPred

0.55

Loss of MoRF binding (P = 0.112);Loss of MoRF binding (P = 0.112);Loss of MoRF binding (P = 0.112);Loss of MoRF binding (P = 0.112);Loss of MoRF binding (P = 0.112);Loss of MoRF binding (P = 0.112);Loss of MoRF binding (P = 0.112);

MVP

0.92

ClinPred

0.97

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.78

gMVP

0.69

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

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