NM_001360.3(DHCR7):c.906C>G (p.Phe302Leu) AND Smith-Lemli-Opitz syndrome

Germline classification:: Pathogenic/Likely pathogenic (7 submissions)
Last evaluated:: Oct 24, 2024
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:: RCV000020440.23

Allele description [Variation Report for NM_001360.3(DHCR7):c.906C>G (p.Phe302Leu)]

NM_001360.3(DHCR7):c.906C>G (p.Phe302Leu)

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.906C>G (p.Phe302Leu)

HGVS:

NC_000011.10:g.71437869G>C
NG_012655.2:g.15563C>G
NM_001163817.2:c.906C>G
NM_001360.3:c.906C>GMANE SELECT
NP_001157289.1:p.Phe302Leu
NP_001351.2:p.Phe302Leu
NP_001351.2:p.Phe302Leu
LRG_340t1:c.906C>G
LRG_340:g.15563C>G
LRG_340p1:p.Phe302Leu
NC_000011.9:g.71148915G>C
NM_001360.2:c.906C>G
c.906C>G (p.Phe302Leu)

Protein change:

F302L

Links:

dbSNP: rs80338858

NCBI 1000 Genomes Browser:

rs80338858

Molecular consequence:

NM_001163817.2:c.906C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001360.3:c.906C>G - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000040855	GeneReviews	no classification provided	not provided	unknown	literature only	PubMed (2) [See all records that cite these PMIDs] 16207203, 20301322
SCV000754771	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 24, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 10814720, 12818773, 14981719, 22226660, 15464432, 28492532
SCV001163697	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001193823	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))	Likely pathogenic (Dec 19, 2019)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 10814720, 15464432, 12818773, 14981719 Citation Link,
SCV001338402	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Feb 19, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 12914579, 23293579, 15776424, 15464432, 14981719, 10814720 Citation Link,
SCV002557799	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 24, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10814720, 35305950, 25741868
SCV002793515	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 24, 2024)	germline	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	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Recent insights into the Smith-Lemli-Opitz syndrome.

Yu H, Patel SB.

Clin Genet. 2005 Nov;68(5):383-91. Review. Erratum in: Clin Genet. 2005 Dec;68(6):570.

PubMed [citation]

PMID:: 16207203
PMCID:: PMC1350989

Smith-Lemli-Opitz Syndrome..

Nowaczyk MJM, Wassif CA.

1998 Nov 13 [updated 2020 Jan 30]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(®) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025.

PubMed [citation]

PMID:: 20301322

See all PubMed Citations (13)

Details of each submission

From GeneReviews, SCV000040855.2

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

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000754771.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 302 of the DHCR7 protein (p.Phe302Leu). This variant is present in population databases (rs80338858, gnomAD 0.01%). This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome, or SLOS (PMID: 10814720, 12818773, 14981719, 22226660; internal data). ClinVar contains an entry for this variant (Variation ID: 21277). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 15464432). 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 Baylor Genetics, SCV001163697.1

#	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 Myriad Genetics, Inc., SCV001193823.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

NM_001360.2(DHCR7):c.906C>G(F302L) is classified as likely pathogenic in the context of Smith-Lemli-Opitz syndrome. Sources cited for classification include the following: PMID 14981719, 10814720, 15464432, 12818773 and 14981719. Classification of NM_001360.2(DHCR7):c.906C>G(F302L) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses and is very rare or not present in genetic databases of healthy individuals. Please note: this variant was assessed in the context of healthy population screening.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001338402.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Variant summary: DHCR7 c.906C>G (p.Phe302Leu) results in a non-conservative amino acid change located in the Loop 6-7 domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251320 control chromosomes (gnomAD). c.906C>G has been reported in the literature as a compound heterozygous genotype in individuals affected with Smith-Lemli-Opitz Syndrome and has been reported as the third most common DHCR7 mutation in Spanish SLOS alleles (example, Yu_2000, Nowaczyk_2004, Ginat_2004, Witsch-Baumgartner_2005). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=4)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely 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 Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002557799.2

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

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Smith-Lemli-Opitz syndrome (MIM#270400). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Exceptionally mild and severe cases have been reported, with intra and interfamilial variable expressivity (PMID: 35305950, GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from phenylalanine to leucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 6 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Ergosterol biosynthesis ERG4_ERG24 domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple individuals with Smith-Lemli-Opitz syndrome (ClinVar, PMIDs: 10814720, 35305950). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_001360.2(DHCR7):c.964-1G>C) in a recessive disease. (SP) 1206 - This variant has been shown to be paternally inherited (by segregation analysis). The proband of this family has been analysed by an external laboratory. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	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, SCV002793515.2

#	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

Last Updated: Apr 7, 2025

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