rs61757582

chr11-71435593-G-Achr11-71435593-G-Cchr11-71435593-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001360.3(DHCR7):c.1210C>T(p.Arg404Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000671 in 1,609,664 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R404G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 35)
  • Exomes 𝑓: 0.000067 (0 hom.)
• Consequence: DHCR7 NM_001360.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13 O:1
• Conservation: PhyloP100: 6.74

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 18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 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 chr11-71435592-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1675468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965
• PP5: Variant 11-71435593-G-A is Pathogenic according to our data. Variant chr11-71435593-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 6788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-71435593-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DHCR7	NM_001360.3	c.1210C>T	p.Arg404Cys	missense_variant	9/9	ENST00000355527.8
DHCR7	NM_001163817.2	c.1210C>T	p.Arg404Cys	missense_variant	9/9
DHCR7	XM_011544777.3	c.1344C>T	p.Pro448=	synonymous_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DHCR7	ENST00000355527.8	c.1210C>T	p.Arg404Cys	missense_variant	9/9	1	NM_001360.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152196 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000373 AC: 9 AN: 241396 Hom.: 0 AF XY: 0.0000303 AC XY: 4 AN XY: 132196

Gnomad AFR exome AF: 0.0000655

Gnomad AMR exome AF: 0.00

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: 0.0000735

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000666 AC: 97 AN: 1457350 Hom.: 0 Cov.: 84 AF XY: 0.0000676 AC XY: 49 AN XY: 725180

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000801

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152314 Hom.: 0 Cov.: 35 AF XY: 0.0000403 AC XY: 3 AN XY: 74484

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000938 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.000164

EpiControl AF: 0.0000594

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Smith-Lemli-Opitz syndrome Pathogenic:7 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 12, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 20, 2020	Variant summary: DHCR7 c.1210C>T (p.Arg404Cys) results in a non-conservative amino acid change located in the Ergosterol biosynthesis ERG4/ERG24 domain (IPR001171) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.7e-05 in 241396 control chromosomes. c.1210C>T has been reported in the literature in multiple individuals affected with Smith-Lemli-Opitz Syndrome (example, Fitzky_1998, Witsch-Baumgartner_2000). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. Both publications reported that expression of p.Arg404Cys in human cell line resulted in similar transcript but reduced protein expression as compared with wildtype (<10%, Fitzky_1998, Witsch-Baumgartner_2000). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 04, 2019	NM_001360.2(DHCR7):c.1210C>T(R404C) is classified as pathogenic in the context of Smith-Lemli-Opitz syndrome and can be associated with mild to severe forms of this disease. Sources cited for classification include the following: PMID 10677299, 22438180, 15954111, and 22438180. Classification of NM_001360.2(DHCR7):c.1210C>T(R404C) 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, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 404 of the DHCR7 protein (p.Arg404Cys). This variant is present in population databases (rs61757582, gnomAD 0.009%). This missense change has been observed in individuals with Smith–Lemli–Opitz syndrome (PMID: 9653161, 10677299, 12818773, 15896653). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6788). 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). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 29, 2022	In vitro expression studies in a human cell line demonstrated that R404C is associated with reduced protein expression (Fitzky, et al, 1998); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15896653, 28250423, 22975760, 29455191, 20301322, 31589614, 33578785, 32058062, 34447666, 28166604, 33836803, 34427008, 9653161) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 17, 2017	- -
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	-	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 13, 2020

The alteration results in an amino acid change:_x000D_ _x000D_ The c.1210C>T (p.R404C) alteration is located in exon 9 (coding exon 7) of the DHCR7 gene. This alteration results from a C to T substitution at nucleotide position 1210, causing the arginine (R) at amino acid position 404 to be replaced by a cysteine (C). The alteration is ultra rare in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the c.1210C>T alteration was observed in 0.0044% (12/272,768) total alleles studied. No homozygotes were reported. The alteration has been observed in affected individuals: _x000D_ _x000D_ This alteration has been reported in multiple patients with Smith Lemli Opitz syndrome (SLOS). The alteration was first reported in a consanguineous family of French origin from Louisiana and was considered a French founder mutation (Fitzky, 1998). Heterologous expression of p.R404C in a human cell line decreased expression of the DHCR7 protein by more than 90% (Fitzky, 1998). Two patients were found to be homozygous for the p.R404C alteration, one died at 6 weeks of age and the other died at one year of age, and another baby with severe SLOS was compound heterozygous for this alteration and IVS8-1G>C (Witsch-Baumgartner, 2000). The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.R404 amino acid is conserved in available vertebrate species. The alteration is predicted deleterious by in silico modeling:_x000D_ _x000D_ The p.R404C alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

DHCR7-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 09, 2023

The DHCR7 c.1210C>T variant is predicted to result in the amino acid substitution p.Arg404Cys. This variant has been documented to be causative for autosomal recessive Smith-Lemli-Optiz Syndrome (Fitzky et al. 1998. PubMed ID: 9653161; Witsch-Baumgartner et al. 2001. PubMed ID: 11175299). It is reported in 0.0083% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-71146639-G-A). It has been interpreted as pathogenic by multiple independent submitters to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/6788). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;D;D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H;H;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-7.5	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		0.99
MVP		0.98
MPC		0.66
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.91
gMVP		0.98

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: rs61757582; hg19: chr11-71146639; COSMIC: COSV100832214; COSMIC: COSV100832214;