rs80338860

Positions:

• chr11-71435749-G-A

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.1054C>T​(p.Arg352Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000018 in 1,611,952 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. R352Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 35)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: DHCR7 NM_001360.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12 U:1 O:1
• Conservation: PhyloP100: 3.92

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 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 chr11-71435748-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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 11-71435749-G-A is Pathogenic according to our data. 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. Variant chr11-71435749-G-A is described in Lovd as [Pathogenic]. Variant chr11-71435749-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DHCR7	NM_001360.3	c.1054C>T	p.Arg352Trp	missense_variant	9/9	ENST00000355527.8
DHCR7	NM_001163817.2	c.1054C>T	p.Arg352Trp	missense_variant	9/9
DHCR7	XM_011544777.3	c.1188C>T	p.Ser396=	synonymous_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DHCR7	ENST00000355527.8	c.1054C>T	p.Arg352Trp	missense_variant	9/9	1	NM_001360.3	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152242 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: 0.00

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: 0.0000120 AC: 3 AN: 248974 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135220

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 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: 0.0000192 AC: 28 AN: 1459710 Hom.: 0 Cov.: 37 AF XY: 0.0000193 AC XY: 14 AN XY: 725960

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152242 Hom.: 0 Cov.: 35 AF XY: 0.0000134 AC XY: 1 AN XY: 74380

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000105 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 16, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2018	Variant summary: DHCR7 c.1054C>T (p.Arg352Trp) results in a non-conservative amino acid change in 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 1.8e-05 in 275158 control chromosomes (gnomAD). The variant, c.1054C>T, has been reported in the literature in multiple individuals affected with Smith-Lemli-Opitz Syndrome (Fitzky_1998, Witsch-Baumgartner_2001, Waterham_2012). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence showing more than 90% reduction in protein expression associated with this variant (Fitzky_1998). 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, no assertion criteria provided	literature only	OMIM	Jan 01, 2001	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 22, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 352 of the DHCR7 protein (p.Arg352Trp). This variant is present in population databases (rs80338860, gnomAD 0.004%). This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 9653161, 15521979, 18006960; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 6787). 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.Arg352 amino acid residue in DHCR7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16044199, 17441222, 21696385). 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, no assertion criteria provided	clinical testing	Counsyl	Jun 14, 2015	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 19, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Jun 30, 2022	Expression studies found that this variant is associated with significantly decreased DHCR7 protein expression (Fitzky BU et al., 1998); Not observed at a 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: 10602371, 15952211, 16207203, 18006960, 16983147, 21696385, 17441222, 16044199, 20301322, 31840946, 22975760, 11175299, 15521979, 9653161, 25040602, 23042628) -

DHCR7-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 30, 2023

The DHCR7 c.1054C>T variant is predicted to result in the amino acid substitution p.Arg352Trp. This variant has been reported alone or with a second DHCR7 variant in individuals with Smith-Lemli-Opitz syndrome (see, for example, Fitzky et al 1998. PubMed ID: 9653161; Witsch-Baumgartner et al 2001. PubMed ID: 11175299; Pappu et al 2006. PubMed ID: 16983147). In vitro experimental studies suggest this variant impacts protein function (Fitzky et al 1998. PubMed ID: 9653161). Alternative nucleotide changes affecting the same amino acid (p.Arg352Gln, p.Arg352Leu) have also been reported in individuals with Smith-Lemli-Opitz syndrome (Witsch-Baumgartner et al. 2000. PubMed ID: 10677299; Al-Owain et al. 2012. PubMed ID: 21696385). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-71146795-G-A). This variant is interpreted as pathogenic. -

Microcephaly Uncertain:1

Uncertain significance, no assertion criteria provided

research

Department of Pediatrics, Samsung Medical Center, Samsung Medical Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D;D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.81	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H;H;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-7.6	D;D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.045	D;D;T
Polyphen		1.0	D;D;.
Vest4		0.98
MVP		0.97
MPC		0.55
ClinPred		1.0	D
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.5
Varity_R		0.93
gMVP		0.97

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: rs80338860; hg19: chr11-71146795;