NM_001360.3(DHCR7):c.1066del (p.His356fs) AND Smith-Lemli-Opitz syndrome

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: Apr 2, 2025
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:: RCV000409736.20

Allele description [Variation Report for NM_001360.3(DHCR7):c.1066del (p.His356fs)]

NM_001360.3(DHCR7):c.1066del (p.His356fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

11q13.4

Genomic location:

Preferred name:

NM_001360.3(DHCR7):c.1066del (p.His356fs)

HGVS:

NC_000011.10:g.71435738del
NC_000011.9:g.71146783del
NG_012655.2:g.17695del
NM_001163817.2:c.1066del
NM_001360.3:c.1066delMANE SELECT
NP_001157289.1:p.His356fs
NP_001351.2:p.His356fs
LRG_340:g.17695del
NC_000011.9:g.71146783del
NC_000011.9:g.71146784del
NC_000011.9:g.71146784delG
NM_001360.2:c.1066delC
NM_001360.3:c.1066delCMANE SELECT

Protein change:

H356fs

Links:

dbSNP: rs774291653

NCBI 1000 Genomes Browser:

rs774291653

Molecular consequence:

NM_001163817.2:c.1066del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001360.3:c.1066del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Smith-Lemli-Opitz syndrome (SLOS)
Synonyms:: LETHAL ACRODYSGENITAL SYNDROME; POLYDACTYLY, SEX REVERSAL, RENAL HYPOPLASIA, AND UNILOBAR LUNG; RSH 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
SCV000485955	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Mar 9, 2016)	unknown	clinical testing	mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf, Citation Link,
SCV001163690	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001471733	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Pathogenic (Feb 3, 2020)	germline	clinical testing	Citation Link,
SCV001589372	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 5, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 18006960, 28492532
SCV002791904	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 4, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV006073374	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 2, 2025)	germline	clinical testing	Citation Link

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Identification of a novel DHCR7 mutation in a Korean patient with Smith-Lemli-Opitz syndrome.

Jong Hee Chae, Ki Joong Kim, Yong Seung Hwang, Ki CS, Kim JW.

J Child Neurol. 2007 Nov;22(11):1297-300.

PubMed [citation]

PMID:: 18006960

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9..

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (3)

Details of each submission

From Counsyl, SCV000485955.2

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV001163690.1

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001471733.1

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

Description

The DHCR7 c.1066delC; p.His356fs variant (rs774291653), to our knowledge, is not reported in the medical literature or gene specific databases in association with Smith-Lemli-Opitz syndrome. This variant is reported in ClinVar (Variation ID: 370598), and is only observed on five alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant results in a premature termination codon in the last exon of the DHCR7 gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated protein that would include a sequence of 57 amino acid residues not usually present. Additionally, several downstream truncating variants have been described in individuals with Smith-Lemli-Opitz syndrome and are considered pathogenic (Cross 2015, Jong Hee Chae 2007, Yan 2019). Based on available information, the p.His356fs variant is considered to be pathogenic. References: Cross JL et al. Determination of the allelic frequency in Smith-Lemli-Opitz syndrome by analysis of massively parallel sequencing data sets. Clin Genet. 2015 Jun;87(6):570-5. Jong Hee Chae et al. Identification of a novel DHCR7 mutation in a Korean patient with Smith-Lemli-Opitz syndrome. J Child Neurol. 2007 Nov;22(11):1297-300. Yan H et al. Targeted next generation sequencing in 112 Chinese patients with intellectual disability/developmental delay: novel mutations and candidate gene. BMC Med Genet. 2019 May 14;20(1):80.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001589372.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change creates a premature translational stop signal (p.His356Thrfs*57) in the DHCR7 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 120 amino acid(s) of the DHCR7 protein. This variant is present in population databases (rs774291653, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with DHCR7-related conditions. ClinVar contains an entry for this variant (Variation ID: 370598). This variant disrupts a region of the DHCR7 protein in which other variant(s) (p.Lys376Argfs*37) have been determined to be pathogenic (PMID: 18006960). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it 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 Fulgent Genetics, Fulgent Genetics, SCV002791904.2

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV006073374.1

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

Description

Variant summary: DHCR7 c.1066delC (p.His356ThrfsX57) results in a premature termination codon, predicted to cause a truncation of the encoded protein. Although, nonsense mediated decay is not predicted, several pathogenic variants are observed downstream. The variant allele was found at a frequency of 1.6e-05 in 249058 control chromosomes. To our knowledge, no occurrence of c.1066delC in individuals affected with Smith-Lemli-Opitz Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 370598). 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

Last Updated: May 3, 2025

ClinVar

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