NM_001360.3(DHCR7):c.964-1G>T AND Smith-Lemli-Opitz syndrome

Germline classification:: Pathogenic/Likely pathogenic (8 submissions)
Last evaluated:: Dec 11, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000383519.21

Allele description [Variation Report for NM_001360.3(DHCR7):c.964-1G>T]

NM_001360.3(DHCR7):c.964-1G>T

Gene:

DHCR7:7-dehydrocholesterol reductase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q13.4

Genomic location:

Preferred name:

NM_001360.3(DHCR7):c.964-1G>T

HGVS:

NC_000011.10:g.71435840C>A
NG_012655.2:g.17592G>T
NM_001163817.2:c.964-1G>T
NM_001360.3:c.964-1G>TMANE SELECT
LRG_340t1:c.964-1G>T
LRG_340:g.17592G>T
NC_000011.9:g.71146886C>A
NM_001163817.1:c.964-1G>T
NM_001360.2:c.964-1G>T

Links:

dbSNP: rs138659167

NCBI 1000 Genomes Browser:

rs138659167

Molecular consequence:

NM_001163817.2:c.964-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001360.3:c.964-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]

Condition(s)

Name:: Smith-Lemli-Opitz syndrome (SLOS)
Synonyms:: LETHAL ACRODYSGENITAL SYNDROME; POLYDACTYLY, SEX REVERSAL, RENAL HYPOPLASIA, AND UNILOBAR LUNG; RUTLEDGE LETHAL MULTIPLE CONGENITAL ANOMALY SYNDROME; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010035; MedGen: C0175694; Orphanet: 818; OMIM: 270400

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000373913	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Likely pathogenic (Apr 27, 2017)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 11427181, 22929031, 20104611 Citation Link,
SCV000793446	Counsyl	no assertion criteria provided	Pathogenic (Aug 16, 2017)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20104611, 22929031, 11427181
SCV000832154	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 11, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 20104611, 17576681, 9536098, 10814720, 10995508, 11427181, 23042628, 28492532
SCV000917276	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Nov 29, 2018)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20104611, 22382802, 22929031 Citation Link,
SCV001163694	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001366807	Centre for Mendelian Genomics, University Medical Centre Ljubljana	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 19, 2019)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002093018	Natera, Inc.	no assertion criteria provided	Pathogenic (May 4, 2017)	germline	clinical testing
SCV002794355	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 27, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]

PMID:: 17576681
PMCID:: PMC1934990

Statistical features of human exons and their flanking regions.

Zhang MQ.

Hum Mol Genet. 1998 May;7(5):919-32.

PubMed [citation]

PMID:: 9536098

See all PubMed Citations (11)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000373913.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Counsyl, SCV000793446.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000832154.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

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‚ÄìLemli‚ÄìOpitz 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000917276.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV001163694.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Centre for Mendelian Genomics, University Medical Centre Ljubljana, SCV001366807.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV002093018.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV002794355.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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