rs80338855

chr11-71441347-G-Achr11-71441347-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_001360.3(DHCR7):c.506C>T(p.Ser169Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,614,112 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S169S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: DHCR7 NM_001360.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10 U:1 O:1
• Conservation: PhyloP100: 8.72

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 Uncertain_significance. Variant got 5 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, 7 uncertain in NM_001360.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-71441347-G-A is Pathogenic according to our data. Variant chr11-71441347-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 21274.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=7, Likely_pathogenic=2, not_provided=1, Uncertain_significance=1}. Variant chr11-71441347-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DHCR7	NM_001360.3	c.506C>T	p.Ser169Leu	missense_variant	6/9	ENST00000355527.8
DHCR7	NM_001163817.2	c.506C>T	p.Ser169Leu	missense_variant	6/9
DHCR7	XM_011544777.3	c.506C>T	p.Ser169Leu	missense_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DHCR7	ENST00000355527.8	c.506C>T	p.Ser169Leu	missense_variant	6/9	1	NM_001360.3	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152224 Hom.: 0 Cov.: 33

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: 0.0000478 AC: 12 AN: 250928 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135698

Gnomad AFR exome AF: 0.0000615

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: 0.0000462

Gnomad NFE exome AF: 0.0000795

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000253 AC: 37 AN: 1461888 Hom.: 0 Cov.: 34 AF XY: 0.0000289 AC XY: 21 AN XY: 727242

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152224 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74366

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: 0.000134 Hom.: 1

Bravo AF: 0.0000416

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:10 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Nov 08, 2021	The DHCR7 c.506C>T variant is a single nucleotide change in exon 6/9 of the DHCR7 gene, which is predicted to change the amino acid serine at position 169 in the protein to leucine. The variant is rare in gnomAD (1/152,224 heterozygotes, 0 homozygotes) (PM2). This variant is detected in trans with the pathogenic DHCR7:c.964-1G>C variant in this patient. The same compound heterozygous genoype has also been reported in at least two other families with a confirmed diagnosis of Smith-Lemli-Opitz syndrome (PMID: 27401223) (PM3_strong). The variant has been identified in at least 7 probands with a clinical presentation of Smith-Lemli-Opitz syndrome; this represents a significant increase in the prevalence of the variant in affected individuals compared with the prevalence in control subjects (PS4_strong). The variant has been reported as pathogenic by other diagnostic laboratories (ClinVar Variation ID: 21274) and has been reported in the HGMD database: CM001124. Computational predictions support a deleterious effect on the gene or gene product (PP3). -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 03, 2020	The DHCR7 c.506C>T, p.Ser169Leu variant (rs80338855) has been reported in multiple patients diagnosed with Smith-Lemli-Opitz syndrome (Correa-Cerro 2005, Witsch-Baumgartner 2000), and found with another pathogenic variant in one individual (Yu 2000). It is listed in ClinVar (Variation ID: 21274), and is observed in the general population databases at a frequency of 0.008 percent in the Exome Variant Server (1/12988 alleles), and 0.005 percent in the Genome Aggregation Database (12/245720 alleles). Based on the high frequency of this variant in published reports of Smith-Lemli-Opitz syndrome, the p.Ser169Leu variant is classified as pathogenic. References: Correa-Cerro L et al. 3beta-hydroxysterol Delta7-reductase and the Smith-Lemli-Opitz syndrome. Mol Genet Metab. 2005; 84(2):112-26. Witsch-Baumgartner M et al. Mutational spectrum in the Delta7-sterol reductase gene and genotype-phenotype correlation in 84 patients with Smith-Lemli-Opitz syndrome. Am J Hum Genet. 2000; 66(2):402-12. Yu H et al. Spectrum of Delta(7)-dehydrocholesterol reductase mutations in patients with the Smith-Lemli-Opitz (RSH) syndrome. Hum Mol Genet. 2000; 9(9):1385-91. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 14, 2020	Variant summary: DHCR7 c.506C>T (p.Ser169Leu) results in a non-conservative amino acid change located in the Transmembrane domain 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 4.8e-05 in 250928 control chromosomes. c.506C>T has been reported in the literature in multiple individuals affected with Smith-Lemli-Opitz Syndrome (example, Yu_2000, Witsch-Baumgartner_2000, Bianconi_2011, Roullet_2012, Quelin_2012, Eroglu_2017). These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect due to the compound heterozygous genotype of the cell line evaluated (Ginat_2004). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Pathogenic, n=1; Likely pathogenic, n=2; VUS, n=1). Some submitters have cited overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 19, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 18, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 26, 2017	The DHCR7 c.506C>T (p.Ser169Leu) missense variant has been reported in at least three studies in which it is found in a total of four individuals with Smith-Lemli-Opitz syndrome (SLOS) in a compound heterozygous state and in nine out of 1,037 disease-associated alleles, none of which were homozygotes, however further details of zygosity are not given (Bianconi et al. 2011; Sparks et al. 2014; Boland et al. 2016; Eroglu et al. (2017). The second variant in the compound heterozygotes was not stated in two of the individuals, was an intron variant in one individual with a mild phenotype and normal IQ and a splice region/intron variant in the fourth individual. The p.Ser169Leu variant is described as one of the 12 most frequent disease-causing variants found at a frequency of 1.7% in patients with SLOS (a total of 10 alleles) (Correa-Cerro et al. 2005; Nowaczyk et al. 2013). Control data are unavailable for this variant, which is reported at a frequency of 0.00012 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Ser169Leu variant is classified as a variant of unknown significance but suspicious for pathogenicity for Smith-Lemli-Opitz syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 169 of the DHCR7 protein (p.Ser169Leu). This variant is present in population databases (rs80338855, gnomAD 0.008%). This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 10814720, 15896653, 21990131, 22226660, 22391996). ClinVar contains an entry for this variant (Variation ID: 21274). 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%. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 09, 2019	NM_001360.2(DHCR7):c.506C>T(S169L) is classified as likely pathogenic in the context of Smith-Lemli-Opitz syndrome. Sources cited for classification include the following: PMID 15464432, 10814720, 22226660, 22391996, 21990131 and 10677299. Classification of NM_001360.2(DHCR7):c.506C>T(S169L) is based on the following criteria: This variant 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	Sep 29, 2022	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2018

The p.S169L pathogenic mutation (also known as c.506C>T), located in coding exon 4 of the DHCR7 gene, results from a C to T substitution at nucleotide position 506. The serine at codon 169 is replaced by leucine, an amino acid with dissimilar properties. This mutation has been identified in conjunction with a second DHCR7 alteration in multiple individuals with Smith-Lemli-Opitz syndrome (Witsch-Baumgartner M et al. Am. J. Hum. Genet., 2000 Feb;66:402-12; Yu H et al. Hum. Mol. Genet., 2000 May;9:1385-91; Ginat S et al. Mol. Genet. Metab., 2004;83:175-83; Bianconi SE et al. Am. J. Med. Genet. A, 2011 Nov;155A:2732-8; Roullet JB et al. J. Inherit. Metab. Dis., 2012 Sep;35:859-69). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 31, 2017

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	D;D;.
Eigen	Benign	0.17
Eigen_PC	Benign	0.056
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.74	D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Benign	1.7	L;L;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Pathogenic	0.71
Sift	Benign	0.033	D;D;D
Sift4G	Uncertain	0.030	D;D;.
Polyphen		0.99	D;D;.
Vest4		0.67
MVP		0.96
MPC		0.50
ClinPred		0.37	T
GERP RS		3.2
Varity_R		0.30
gMVP		0.92

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: rs80338855; hg19: chr11-71152393;