NM_001360.3(DHCR7):c.852C>A (p.Phe284Leu) AND Smith-Lemli-Opitz syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Dec 2, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000815482.8

Allele description [Variation Report for NM_001360.3(DHCR7):c.852C>A (p.Phe284Leu)]

NM_001360.3(DHCR7):c.852C>A (p.Phe284Leu)

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.852C>A (p.Phe284Leu)

HGVS:

NC_000011.10:g.71437923G>T
NG_012655.2:g.15509C>A
NM_001163817.2:c.852C>A
NM_001360.3:c.852C>AMANE SELECT
NP_001157289.1:p.Phe284Leu
NP_001351.2:p.Phe284Leu
NP_001351.2:p.Phe284Leu
LRG_340t1:c.852C>A
LRG_340:g.15509C>A
LRG_340p1:p.Phe284Leu
NC_000011.9:g.71148969G>T
NM_001360.2:c.852C>A

Note:

ClinGen staff contributed the HGVS expression for this variant.

Protein change:

F284L; PHE284LEU

Links:

OMIM: 602858.0019; dbSNP: rs184297154

NCBI 1000 Genomes Browser:

rs184297154

Molecular consequence:

NM_001163817.2:c.852C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001360.3:c.852C>A - 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; 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
SCV000027391	OMIM	no assertion criteria provided	Pathogenic (Nov 15, 2003)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 10814720, 14556255
SCV000955938	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 2, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10814720, 16983147, 28492532
SCV002093024	Natera, Inc.	no assertion criteria provided	Likely pathogenic (Feb 8, 2021)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000027391

OMIM

no assertion criteria provided

Pathogenic
(Nov 15, 2003)

germline

literature only

PubMed (2)
[See all records that cite these PMIDs]

SCV000955938

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 2, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV002093024

Natera, Inc.

no assertion criteria provided

Likely pathogenic
(Feb 8, 2021)

germline

clinical testing

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	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Normal cognition and behavior in a Smith-Lemli-Opitz syndrome patient who presented with Hirschsprung disease.

Mueller C, Patel S, Irons M, Antshel K, Salen G, Tint GS, Bay C.

Am J Med Genet A. 2003 Nov 15;123A(1):100-6.

PubMed [citation]

PMID:: 14556255
PMCID:: PMC1201564

Spectrum of Delta(7)-dehydrocholesterol reductase mutations in patients with the Smith-Lemli-Opitz (RSH) syndrome.

Yu H, Lee MH, Starck L, Elias ER, Irons M, Salen G, Patel SB, Tint GS.

Hum Mol Genet. 2000 May 22;9(9):1385-91. Erratum in: Hum Mol Genet 2000 Jul 22;9(12):1903.

PubMed [citation]

PMID:: 10814720

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000027391.2

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

Description

In a patient with very mild Smith-Lemli-Opitz syndrome (SLOS; 270400), Yu et al. (2000) identified compound heterozygosity for 2 mutations in the DHCR7 gene: phe284 to leu (F284L), just outside the transmembrane domain on exon 8, and the more common val326 to leu (V326L; 602858.0011), in the transmembrane domain on exon 9. Mueller et al. (2003) described the clinical features of this patient. Developmentally, the child demonstrated mild delays in gross motor skills associated with mild hypotonia. Cognitive, language, and motor abilities were all within the low average range for her age, between the 14th and 18th centiles. She had not demonstrated temper tantrums, motor stereotypes, sleep disturbance, or hypersensitivity to light and sound as shown by many SLOS patients. The patient had presented at 12 days of age with poor feeding, abdominal distention, and jaundice. Colonic biopsy was consistent with Hirschsprung disease. Physical examination showed subtle 2,3 syndactyly. Her 7-dehydrocholesterol level was markedly elevated, and her cholesterol level was normal. Cholesterol supplementation implemented at 3 months of age resulted in increased cholesterol levels and reduced dehydrocholesterol levels. MRI of the brain showed no abnormalities.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000955938.4

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

Description

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. ClinVar contains an entry for this variant (Variation ID: 658626). This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 10814720, 16983147). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 284 of the DHCR7 protein (p.Phe284Leu). 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 Natera, Inc., SCV002093024.1

#	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

Last Updated: Sep 29, 2024

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