11-71435575-C-T

Position:

• chr11-71435575-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001360.3(DHCR7):​c.1228G>A​(p.Gly410Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000335 in 1,610,856 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 Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 35)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: DHCR7 NM_001360.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13 O:1
• Conservation: PhyloP100: 6.89

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 11-71435575-C-T is Pathogenic according to our data. Variant chr11-71435575-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 21272.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-71435575-C-T is described in Lovd as [Pathogenic]. Variant chr11-71435575-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DHCR7	NM_001360.3	c.1228G>A	p.Gly410Ser	missense_variant	9/9	ENST00000355527.8	NP_001351.2
DHCR7	NM_001163817.2	c.1228G>A	p.Gly410Ser	missense_variant	9/9		NP_001157289.1
DHCR7	XM_011544777.3	c.1362G>A	p.Ser454Ser	synonymous_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DHCR7	ENST00000355527.8	c.1228G>A	p.Gly410Ser	missense_variant	9/9	1	NM_001360.3	ENSP00000347717.4
DHCR7	ENST00000685320.1	c.643G>A	p.Gly215Ser	missense_variant	8/8			ENSP00000509319.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152220 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000731 AC: 18 AN: 246180 Hom.: 0 AF XY: 0.0000447 AC XY: 6 AN XY: 134098

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000319

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000448

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000343 AC: 50 AN: 1458636 Hom.: 0 Cov.: 85 AF XY: 0.0000386 AC XY: 28 AN XY: 725740

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000306

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152220 Hom.: 0 Cov.: 35 AF XY: 0.0000403 AC XY: 3 AN XY: 74368

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000425 Hom.: 0

Bravo AF: 0.0000453

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Smith-Lemli-Opitz syndrome Pathogenic:8 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 08, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 12, 2019	NM_001360.2(DHCR7):c.1228G>A(G410S) is classified as pathogenic in the context of Smith-Lemli-Opitz syndrome. Sources cited for classification include the following: PMID 9653161, 15877207, 10896306, 10814720, 15952211, 12818773, 15896653 and 22391996. Classification of NM_001360.2(DHCR7):c.1228G>A(G410S) 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. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Smith-Lemli-Opitz syndrome (MIM#270400). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Exceptionally mild and severe cases have been reported, with intra and interfamilial variable expressivity (PMID: 35305950). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2 & v3: 22 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2 & v3: 2 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated ERG4_ERG24 domain (DECIPHER). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It has been identified in individuals with Smith-Lemli-Opitz syndrome (PMID: 23042628) and it is regarded as likely pathogenic or pathogenic by multiple diagnostic laboratories in ClinVar. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 10, 2024	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 410 of the DHCR7 protein (p.Gly410Ser). This variant is present in population databases (rs80338862, gnomAD 0.03%). This missense change has been observed in individuals with Smith-Lemli-Opitz syndrome (PMID: 9653161, 12818773, 15896653). ClinVar contains an entry for this variant (Variation ID: 21272). 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%. Experimental studies have shown that this missense change affects DHCR7 function (PMID: 9653161). This variant disrupts the p.Gly410 amino acid residue in DHCR7. Other variant(s) that disrupt this residue have been observed in individuals with DHCR7-related conditions (PMID: 10677299), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 04, 2017	Variant summary: The DHCR7 c.1228G>A (p.Gly410Ser) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in the large control database ExAC at a frequency of 0.000043 (5/116304 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic DHCR7 variant (0.0043301). In the literature, the variant has been identified in several patients with SLOS in compound heterozygous state with other pathogenic/likely pathogenic mutations as well as in homozygous state (e.g., Kolejakova_Gen Physiol Biophys_2009; Kalb_Clin Genet_2012). Cell-based functional studies have been performed that revealed a severe reduction in protein expression and enzyme activity due to the variant (Fitzky_PNAS_1998; Shim_BBRC_2004). The variant also lies at one of the transmembrane regions of the protein, where many known pathogenic mutations are located (Fitzky_PNAS_1998). In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 18, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -

not provided Pathogenic:4

Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 30, 2020	Expression studies in a human cell line found that G410S reduced DHCR7 protein expression by greater than 90% compared to wild-type (Fitzky et al., 1998); 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: 31589614, 31840946, 31395954, 17237122, 22391996, 20301322, 27415407, 28166604, 19390132, 15952211, 22211794, 22226660, 25405082, 15013448, 9653161, 22975760, 23042628) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 06, 2013	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 22, 2022

The c.1228G>A (p.G410S) alteration is located in exon 9 (coding exon 7) of the DHCR7 gene. This alteration results from a G to A substitution at nucleotide position 1228, causing the glycine (G) at amino acid position 410 to be replaced by a serine (S). Based on data from gnomAD, the A allele has an overall frequency of 0.007% (18/246180) total alleles studied. The highest observed frequency was 0.032% (11/34440) of Latino alleles. This alteration has been detected in both the homozygous and compound heterozygous states in multiple individuals with Smith-Lemli-Opitz syndrome (SLOS) (Schoner, 2020; Wojcik, 2019; Kalb, 2012; Haas, 2007; Boland, 2016; Kolejáková, 2009; Scalco, 2005; Babovic-Vuksanovic, 2005; Wassif, 2005; Shim, 2004; Yu, 2000; Kozak, 2000; Fitzky,1998). This amino acid position is highly conserved in available vertebrate species. In two separate functional studies, this alteration was shown to reduce DHCR7 protein expression and enzymatic activity (Fitzky, 1998; Shim, 2004). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D;D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	.;D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H;H;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.7	D;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.96
MutPred		0.91		Loss of catalytic residue at G410 (P = 0.032);Loss of catalytic residue at G410 (P = 0.032);.;
MVP		0.98
MPC		0.57
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.92
gMVP		0.95

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

LitVar

Other links and lift over

dbSNP: rs80338862; hg19: chr11-71146621;