rs104886041

Variant names:

• chr11-71444018-A-G
• rs104886041
• NM_001360.3:c.296T>C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_001360.3(DHCR7):​c.296T>C​(p.Leu99Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,460,672 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 (★★). Synonymous variant affecting the same amino acid position (i.e. L99L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: DHCR7 NM_001360.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.77
• Publications: 5 publications found

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)

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_001360.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 11-71444018-A-G is Pathogenic according to our data. Variant chr11-71444018-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 553296.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	c.296T>C	p.Leu99Pro	missense_variant	Exon 4 of 9	ENST00000355527.8	NP_001351.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHCR7	ENST00000355527.8	c.296T>C	p.Leu99Pro	missense_variant	Exon 4 of 9	1	NM_001360.3	ENSP00000347717.4
DHCR7	ENST00000685320.1	c.-290T>C		5_prime_UTR_variant	Exon 3 of 8			ENSP00000509319.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249078 AF XY: 0.00

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: 0.00000889

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1460672 Hom.: 0 Cov.: 30 AF XY: 0.0000124 AC XY: 9 AN XY: 726578

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26040

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86066

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53176

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1111482

Other (OTH) AF: 0.00 AC: 0 AN: 60338

GnomAD4 genome Cov.: 33

Alfa AF: 0.000146 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Smith-Lemli-Opitz syndrome Pathogenic:2

Aug 15, 2017

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. -

Sep 05, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. ClinVar contains an entry for this variant (Variation ID: 553296). This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 9653161, 16181459). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs104886041, gnomAD 0.0009%). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 99 of the DHCR7 protein (p.Leu99Pro). Experimental studies have shown that this missense change affects DHCR7 function (PMID: 9653161). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Dec 01, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 10, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect [variant reduced DHCR7 protein expression of to less than 10% of wildtype] (PMID: 9653161); Not observed at 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: 31840946, 16181459, 10814720, 11175299, 9653161) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D;.;T;T;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.79	.;T;T;T;T;T
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M;M;.;.;.;.
PhyloP100		7.8
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.1	D;D;D;D;D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.010	D;D;D;D;D;D
Sift4G	Uncertain	0.0080	D;D;.;.;D;.
Polyphen		0.97	D;D;.;.;.;.
Vest4		0.87
MutPred		0.83		Loss of stability (P = 0.0308);Loss of stability (P = 0.0308);.;Loss of stability (P = 0.0308);Loss of stability (P = 0.0308);Loss of stability (P = 0.0308);
MVP		0.95
MPC		0.63
ClinPred		0.94	D
GERP RS		4.5
Varity_R		0.67
gMVP		0.95
Mutation Taster		=4/96	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104886041; hg19: chr11-71155064;