11-71435815-C-T

Position:

chr11-71435815-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001360.3(DHCR7):c.988G>A(p.Val330Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000411 in 1,603,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 35)

Exomes 𝑓: 0.00041 ( 0 hom. )

Consequence

DHCR7
NM_001360.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:12

Conservation

PhyloP100: 3.28

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:

DHCR7 (HGNC:):

DHCR7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.39428446).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DHCR7	NM_001360.3 linkuse as main transcript	c.988G>A	p.Val330Met	missense_variant	9/9	ENST00000355527.8	NP_001351.2	Q9UBM7A0A024R5F7
DHCR7	NM_001163817.2 linkuse as main transcript	c.988G>A	p.Val330Met	missense_variant	9/9		NP_001157289.1	Q9UBM7A0A024R5F7
DHCR7	XM_011544777.3 linkuse as main transcript	c.1122G>A	p.Pro374Pro	synonymous_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DHCR7	ENST00000355527.8 linkuse as main transcript	c.988G>A	p.Val330Met	missense_variant	9/9	1	NM_001360.3	ENSP00000347717.4		Q9UBM7
DHCR7	ENST00000685320.1 linkuse as main transcript	c.403G>A	p.Val135Met	missense_variant	8/8			ENSP00000509319.1		B4E1K5

Frequencies

GnomAD3 genomes

AF:

0.000427

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000485

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000364

AC:

AN:

239088

Hom.:

AF XY:

0.000367

AC XY:

AN XY:

130966

show subpopulations

Gnomad AFR exome

AF:

0.000268

Gnomad AMR exome

AF:

0.000643

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000557

Gnomad SAS exome

AF:

0.0000331

Gnomad FIN exome

AF:

0.000103

Gnomad NFE exome

AF:

0.000496

Gnomad OTH exome

AF:

0.000679

GnomAD4 exome

AF:

0.000409

AC:

594

AN:

1451442

Hom.:

Cov.:

AF XY:

0.000420

AC XY:

303

AN XY:

720604

show subpopulations

Gnomad4 AFR exome

AF:

0.0000900

Gnomad4 AMR exome

AF:

0.000651

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.0000233

Gnomad4 FIN exome

AF:

0.000337

Gnomad4 NFE exome

AF:

0.000455

Gnomad4 OTH exome

AF:

0.000400

GnomAD4 genome

AF:

0.000427

AC:

AN:

152322

Hom.:

Cov.:

AF XY:

0.000457

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000485

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000250

Hom.:

Bravo

AF:

0.000370

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.000467

AC:

ExAC

AF:

0.000330

AC:

EpiCase

AF:

0.000654

EpiControl

AF:

0.000771

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Smith-Lemli-Opitz syndrome

Uncertain:6

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 25, 2022	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 330 of the DHCR7 protein (p.Val330Met). This variant is present in population databases (rs139724817, gnomAD 0.06%). This missense change has been observed in individual(s) with Smith‚ÄìLemli‚ÄìOpitz syndrome (PMID: 12270273). ClinVar contains an entry for this variant (Variation ID: 420113). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	May 11, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 23, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 19, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 07, 2022	Reported previously in an individual with psychomotor regression and multiple congenital abnormalities suggestive of Smith-Lemli-Opitz syndrome who had a second DHCR7 variant identified on the opposite allele; however, this patient's serum 7-DHC concentration was 100 fold lower than typical mean serum levels for affected individuals, and significantly lower than in the other patients reported in the study (Patrono et al., 2002); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23042628, 29300326, 24813812, 27401223, 15670717, 28250423, 12270273, 34426522) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 23, 2021	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 11, 2022

Variant summary: DHCR7 c.988G>A (p.Val330Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00036 in 239088 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in DHCR7 causing Smith-Lemli-Opitz Syndrome (0.00036 vs 0.0043), allowing no conclusion about variant significance. c.988G>A has been reported in the literature in individuals affected with Smith-Lemli-Opitz Syndrome (example, Patrono_2002) and autism (example, Saskin_2017). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submissions (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hepatoblastoma

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Molecular Oncology - Human Genetics Lab, University of Sao Paulo

- -

DHCR7-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 16, 2024

The DHCR7 c.988G>A variant is predicted to result in the amino acid substitution p.Val330Met. This variant has been reported in a patient with suspected Smith-Lemli-Opitz syndrome (Patrono et al. 2002. PubMed ID: 12270273), in two patients in a large autism cohort (Table S2, Saskin et al. 2017. PubMed ID: 28250423), and in two patients with hepatoblastoma (Aguiar et al. 2022. PubMed ID: 35495172). In all cases pathogenicity was not clearly established. This variant is reported in 0.066% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

D;D;D

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.95

.;D;D

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.39

T;T;T

MetaSVM

Pathogenic

0.88

MutationAssessor

Pathogenic

3.3

M;M;.

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-2.1

N;N;N

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0050

D;D;D

Sift4G

Uncertain

0.025

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.82

MVP

0.93

MPC

0.55

ClinPred

0.28

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.32

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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