NM_001360.3(DHCR7):c.730G>A (p.Gly244Arg) AND Smith-Lemli-Opitz syndrome

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: Jun 17, 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:: RCV000007183.18

Allele description [Variation Report for NM_001360.3(DHCR7):c.730G>A (p.Gly244Arg)]

NM_001360.3(DHCR7):c.730G>A (p.Gly244Arg)

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.730G>A (p.Gly244Arg)

HGVS:

NC_000011.10:g.71438980C>T
NG_012655.2:g.14452G>A
NM_001163817.2:c.730G>A
NM_001360.3:c.730G>AMANE SELECT
NP_001157289.1:p.Gly244Arg
NP_001351.2:p.Gly244Arg
NP_001351.2:p.Gly244Arg
LRG_340t1:c.730G>A
LRG_340:g.14452G>A
LRG_340p1:p.Gly244Arg
NC_000011.9:g.71150026C>T
NM_001360.2:c.730G>A
Q9UBM7:p.Gly244Arg

Protein change:

G244R; GLY244ARG

Links:

UniProtKB: Q9UBM7#VAR_012722; OMIM: 602858.0006; dbSNP: rs121909764

NCBI 1000 Genomes Browser:

rs121909764

Molecular consequence:

NM_001163817.2:c.730G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001360.3:c.730G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000027379	OMIM	no assertion criteria provided	Pathogenic (Aug 1, 1998)	germline	literature only	Waterham, H. R., Wijburg, F. A., Hennekam, R. C. M., Vreken, P., Poll-The, B. T., Dorland, L., Duran, M., Jira, P. E., Smeitink, J. A. M., Wevers, R. A., Wanders, R. J. A. Smith-Lemli-Opitz syndrome is caused by mutations in the 7-dehydrocholesterol reductase gene. Am. J. Hum. Genet. 63: 329-338, 1998.,
SCV000941238	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 15, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 9683613, 12270273, 12818773, 23293579, 28492532
SCV001163701	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002059016	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 3, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] PMID:9683613,
SCV002093030	Natera, Inc.	no assertion criteria provided	Pathogenic (Dec 28, 2020)	germline	clinical testing
SCV005629862	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 17, 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	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Smith-Lemli-Opitz syndrome is caused by mutations in the 7-dehydrocholesterol reductase gene.

Waterham HR, Wijburg FA, Hennekam RC, Vreken P, Poll-The BT, Dorland L, Duran M, Jira PE, Smeitink JA, Wevers RA, Wanders RJ.

Am J Hum Genet. 1998 Aug;63(2):329-38.

PubMed [citation]

PMID:: 9683613
PMCID:: PMC1377322

Two novel mutations of the human delta7-sterol reductase (DHCR7) gene in children with Smith-Lemli-Opitz syndrome.

Patrono C, Dionisi-Vici C, Giannotti A, Bembi B, Digilio MC, Rizzo C, Purificato C, Martini C, Pierini R, Santorelli FM.

Mol Cell Probes. 2002 Aug;16(4):315-8.

PubMed [citation]

PMID:: 12270273

See all PubMed Citations (6)

Details of each submission

From OMIM, SCV000027379.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	not provided

Description

For discussion of the gly244-to-arg (G244R) mutation in the DHCR7 gene that was found in compound heterozygous state in a patient with Smith-Lemli-Opitz syndrome (SLOS; 270400) by Waterham et al. (1998), see 602858.0005.

#	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, SCV000941238.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 244 of the DHCR7 protein (p.Gly244Arg). This variant is present in population databases (rs121909764, gnomAD 0.02%). This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 9683613, 12270273, 12818773, 23293579). ClinVar contains an entry for this variant (Variation ID: 6781). 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 with a positive predictive value of 95%. 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, SCV001163701.1

#	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 3billion, SCV002059016.1

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

Description

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000006781, PMID:9683613, PS1_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.972, 3CNET: 0.993, PP3_P). A missense variant is a common mechanism associated with Smith-Lemli-Opitz syndrome (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000032, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.

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

From Natera, Inc., SCV002093030.1

#	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, SCV005629862.1

#	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

Last Updated: Apr 20, 2025

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