NM_001360.3(DHCR7):c.1139G>A (p.Cys380Tyr) AND Smith-Lemli-Opitz syndrome

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: Nov 7, 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:: RCV000169472.16

Allele description [Variation Report for NM_001360.3(DHCR7):c.1139G>A (p.Cys380Tyr)]

NM_001360.3(DHCR7):c.1139G>A (p.Cys380Tyr)

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.1139G>A (p.Cys380Tyr)

HGVS:

NC_000011.10:g.71435664C>T
NG_012655.2:g.17768G>A
NM_001163817.2:c.1139G>A
NM_001360.3:c.1139G>AMANE SELECT
NP_001157289.1:p.Cys380Tyr
NP_001351.2:p.Cys380Tyr
NP_001351.2:p.Cys380Tyr
LRG_340t1:c.1139G>A
LRG_340:g.17768G>A
LRG_340p1:p.Cys380Tyr
NC_000011.9:g.71146710C>T
NM_001360.2:c.1139G>A
Q9UBM7:p.Cys380Tyr
c.1139G>A (p.Cys380Tyr)

Protein change:

C380Y

Links:

UniProtKB: Q9UBM7#VAR_023175; dbSNP: rs779709646

NCBI 1000 Genomes Browser:

rs779709646

Molecular consequence:

NM_001163817.2:c.1139G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001360.3:c.1139G>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
SCV000220916	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Nov 25, 2014)	unknown	literature only	PubMed (6) [See all records that cite these PMIDs] 17994283, 15896653, 16983147, 17497248, 10677299, 12070263 Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015), Citation Link,
SCV000803782	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne - Clinvar_gadteam_Clinical_exome_analysis_3	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 11, 2017)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001163687	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001225668	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 7, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 10677299, 25405082, 15896653, 17441222, 28492532
SCV002093008	Natera, Inc.	no assertion criteria provided	Pathogenic (Mar 17, 2017)	germline	clinical testing
SCV002779328	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 8, 2022)	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, literature only

Citations

PubMed

Molecular screening of Smith-Lemli-Opitz syndrome in pregnant women from the Czech Republic.

Blahakova I, Makaturova E, Kotrbova L, Soukupova M, Lastuvkova J, Kozak L.

J Inherit Metab Dis. 2007 Nov;30(6):964-9. Epub 2007 Nov 12.

PubMed [citation]

PMID:: 17994283

Increased nonsterol isoprenoids, dolichol and ubiquinone, in the Smith-Lemli-Opitz syndrome: effects of dietary cholesterol.

Pappu AS, Connor WE, Merkens LS, Jordan JM, Penfield JA, Illingworth DR, Steiner RD.

J Lipid Res. 2006 Dec;47(12):2789-98. Epub 2006 Sep 18.

PubMed [citation]

PMID:: 16983147

See all PubMed Citations (10)

Details of each submission

From Counsyl, SCV000220916.2

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

#	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 Equipe Genetique des Anomalies du Developpement, Université de Bourgogne - Clinvar_gadteam_Clinical_exome_analysis_3, SCV000803782.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV001163687.1

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001225668.5

#	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 cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 380 of the DHCR7 protein (p.Cys380Tyr). This variant is present in population databases (rs779709646, gnomAD 0.0009%). This missense change has been observed in individual(s) with Smith‚ÄìLemli‚ÄìOpitz syndrome (PMID: 10677299, 15896653, 25405082). ClinVar contains an entry for this variant (Variation ID: 189069). 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%. This variant disrupts the p.Cys380 amino acid residue in DHCR7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15896653, 17441222). This suggests that this residue is clinically significant, and that variants that disrupt this residue 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 Natera, Inc., SCV002093008.1

#	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, SCV002779328.1

#	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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