11-71435840-C-A

Position:

• chr11-71435840-C-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001360.3(DHCR7):​c.964-1G>T variant causes a splice acceptor change. The variant allele was found at a frequency of 0.0000444 in 1,599,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 35)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: DHCR7 NM_001360.3 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-71435840-C-A is Pathogenic according to our data. Variant chr11-71435840-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 305956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-71435840-C-A is described in Lovd as [Likely_pathogenic]. Variant chr11-71435840-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DHCR7	NM_001360.3	c.964-1G>T		splice_acceptor_variant		ENST00000355527.8	NP_001351.2
DHCR7	NM_001163817.2	c.964-1G>T		splice_acceptor_variant			NP_001157289.1
DHCR7	XM_011544777.3	c.1097G>T	p.Arg366Met	missense_variant	9/9		XP_011543079.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DHCR7	ENST00000355527.8	c.964-1G>T		splice_acceptor_variant		1	NM_001360.3	ENSP00000347717	P1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152210 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: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000563 AC: 13 AN: 230702 Hom.: 0 AF XY: 0.0000627 AC XY: 8 AN XY: 127518

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: 0.00

Gnomad FIN exome AF: 0.000615

Gnomad NFE exome AF: 0.0000290

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000435 AC: 63 AN: 1447660 Hom.: 0 Cov.: 36 AF XY: 0.0000417 AC XY: 30 AN XY: 718898

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000277

Gnomad4 NFE exome AF: 0.0000434

Gnomad4 OTH exome AF: 0.0000334

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152210 Hom.: 0 Cov.: 35 AF XY: 0.0000538 AC XY: 4 AN XY: 74348

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: 0.0000941

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000491

ExAC AF: 0.0000498 AC: 6

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Smith-Lemli-Opitz syndrome Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 27, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Aug 16, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The DHCR7 c.964-1G>T variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.964-1G>T variant, which is also described as IVS8-1G>T, has been reported in two studies in which it is identified in three patients with Smith-Lemli-Opitz syndrome (SLOS), including one homozygote and two compound heterozygotes (Jira et al. 2001; Weaver et al. 2008; Lanthaler et al. 2013). This variant was also found in a heterozygous state in the father of one patient, who had abnormally low cholesterol levels. Control data are unavailable for this variant, which is reported at a frequency of 0.00666 in the European (Finnish) population of the Exome Aggregation Consortium database. Jira et al. (2001) noted that the c.964-1G>T variant occurs at the same position as the known pathogenic c.964-1G>C splice acceptor variant, which accounts for over 28% of all disease-causing alleles in SLOS. The c.964-1G>C variant disrupts the splice acceptor site of intron eight, which leads to the insertion of 134 base pairs of intronic sequence into the DHCR7 mRNA causing a frameshift and premature truncation, ultimately resulting in a non-functional protein product. The c.964-1G>T variant is predicted to result in the same non-functional protein. Based on the evidence and due to the potential impact of splice acceptor variants, the c.964-1G>T variant is classified as likely pathogenic 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	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 11, 2023	This sequence change affects an acceptor splice site in intron 8 of the DHCR7 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs138659167, gnomAD 0.05%). Disruption of this splice site has been observed in individuals with Smith–Lemli–Opitz Syndrome (PMID: 11427181, 20104611). ClinVar contains an entry for this variant (Variation ID: 305956). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the c.964-1G nucleotide in the DHCR7 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 10814720, 10995508, 11427181, 23042628). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	May 04, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Aug 19, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 29, 2018	Variant summary: DHCR7 c.964-1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6.6e-05 in 259000 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in DHCR7 causing Smith-Lemli-Opitz Syndrome (6.6e-05 vs 0.0043), allowing no conclusion about variant significance. The variant, c.964-1G>T, has been reported in the literature in compound heterozygote and homozygote individuals affected with Smith-Lemli-Opitz Syndrome (Jira_2001, Weaver_2010, Lanthaler_2013). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 29, 2024	Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25525159, 28166604, 11427181, 23042628, 20104611, 9653161, 21777499, 22929031) -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 29, 2021

The c.964-1G>T intronic alteration consists of a G to T substitution one nucleotide before coding exon 7 of the DHCR7 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). Based on data from gnomAD, the T allele has an overall frequency of 0.01% (17/262084) total alleles studied. The highest observed frequency was 0.05% (10/19724) of European (Finnish) alleles. This variant has been reported in the homozygous and compound heterozygous states in patients with Smith-Lemli-Opitz syndrome (SLOS) (Jira, 2001; Weaver, 2010; Lanthaler, 2013). In addition, another variant at this position (c.964-1G>C) is one of the most common DHCR7 mutations associated with SLOS (Witsch-Baumgartner, 2008). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. 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

Apr 13, 2023

The DHCR7 c.964-1G>T variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant was reported in an individual with Smith-Lemli-Opitz syndrome (described as IVS8-1G>T, Jira et al. 2001. PubMed ID: 11427181). This variant is reported in 0.051% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-71146886-C-A). Variants that disrupt the consensus splice acceptor site in DHCR7 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.97	D
MutationTaster	Benign	1.0	D;D
ClinPred		0.46	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.56		Position offset: -31
DS_AL_spliceai		0.99		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs138659167; hg19: chr11-71146886;