11-71435748-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM5 PP5_Very_Strong

The NM_001360.3(DHCR7):c.1055G>A(p.Arg352Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000018 in 1,612,012 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R352W) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 35)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: DHCR7 NM_001360.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 6.88

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 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, 3 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 chr11-71435749-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 6787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 11-71435748-C-T is Pathogenic according to our data. Variant chr11-71435748-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 6795.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-71435748-C-T is described in Lovd as [Pathogenic]. Variant chr11-71435748-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DHCR7	NM_001360.3	c.1055G>A	p.Arg352Gln	missense_variant	9/9	ENST00000355527.8
DHCR7	NM_001163817.2	c.1055G>A	p.Arg352Gln	missense_variant	9/9
DHCR7	XM_011544777.3	c.1189G>A	p.Gly397Arg	missense_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DHCR7	ENST00000355527.8	c.1055G>A	p.Arg352Gln	missense_variant	9/9	1	NM_001360.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152234 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

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

GnomAD3 exomes AF: 0.0000241 AC: 6 AN: 248990 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135224

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000547

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1459660 Hom.: 0 Cov.: 37 AF XY: 0.0000138 AC XY: 10 AN XY: 725918

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152352 Hom.: 0 Cov.: 35 AF XY: 0.0000134 AC XY: 1 AN XY: 74504

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000308 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Smith-Lemli-Opitz syndrome Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2005	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 15, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 352 of the DHCR7 protein (p.Arg352Gln). This variant is present in population databases (rs121909768, gnomAD 0.01%). This missense change has been observed in individual(s) with DHCR7-related conditions (PMID: 10677299, 21696385). ClinVar contains an entry for this variant (Variation ID: 6795). 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%. 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: 9653161, 15521979, 18006960; Invitae). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 17, 2019	NM_001360.2(DHCR7):c.1055G>A(R352Q) is classified as pathogenic in the context of Smith-Lemli-Opitz syndrome and is associated with moderate or mild forms of this disease. Sources cited for classification include the following: PMID 16044199, 21696385, 20556518, 10677299 and 17441222. Classification of NM_001360.2(DHCR7):c.1055G>A(R352Q) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 10, 2022	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 30, 2021	Published functional studies demonstrate reduced protein expression compared to wild-type (Prabhu et al., 2016); 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; In addition, in silico splice predictors suggest this variant may lead to abnormal gene splicing; This variant is associated with the following publications: (PMID: 22975760, 16044199, 27401223, 27415407, 28166604, 21696385, 20556518, 18006960, 17441222, 9653161, 15521979, 27535533, 33836803, 26887953, 10677299) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 31, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	34
Dann	Uncertain	0.99
DEOGEN2	Benign	0.23	T
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.35	T
M_CAP	Pathogenic	0.33	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	A;A
PROVEAN	Benign	0.060	N
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D
MutPred		0.15		Gain of solvent accessibility (P = 0.019);
MVP		0.87
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.34		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.34		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121909768; hg19: chr11-71146794;