NM_001360.3(DHCR7):c.866C>T (p.Thr289Ile) AND Smith-Lemli-Opitz syndrome

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Jan 4, 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:: RCV000007191.14

Allele description [Variation Report for NM_001360.3(DHCR7):c.866C>T (p.Thr289Ile)]

NM_001360.3(DHCR7):c.866C>T (p.Thr289Ile)

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.866C>T (p.Thr289Ile)

HGVS:

NC_000011.10:g.71437909G>A
NG_012655.2:g.15523C>T
NM_001163817.2:c.866C>T
NM_001360.3:c.866C>TMANE SELECT
NP_001157289.1:p.Thr289Ile
NP_001351.2:p.Thr289Ile
NP_001351.2:p.Thr289Ile
LRG_340t1:c.866C>T
LRG_340:g.15523C>T
LRG_340p1:p.Thr289Ile
NC_000011.9:g.71148955G>A
NM_001360.2:c.866C>T
Q9UBM7:p.Thr289Ile

Protein change:

T289I; THR289ILE

Links:

UniProtKB: Q9UBM7#VAR_012725; OMIM: 602858.0015; dbSNP: rs121909765

NCBI 1000 Genomes Browser:

rs121909765

Molecular consequence:

NM_001163817.2:c.866C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001360.3:c.866C>T - 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
SCV000027387	OMIM	no assertion criteria provided	Pathogenic (Apr 22, 2001)	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 9714007, 10995508, 11298379
SCV000486161	Counsyl	no assertion criteria provided	Likely pathogenic (Apr 6, 2016)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24500076, 10995508
SCV001163698	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001203505	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 4, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10995508, 11298379, 28492532

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
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

Smith-Lemli-Opitz syndrome: phenotypic extreme with minimal clinical findings.

Nowaczyk MJ, Whelan DT, Hill RE.

Am J Med Genet. 1998 Aug 6;78(5):419-23.

PubMed [citation]

PMID:: 9714007

Decreased cerebral spinal fluid neurotransmitter levels in Smith-Lemli-Opitz syndrome.

Sparks SE, Wassif CA, Goodwin H, Conley SK, Lanham DC, Kratz LE, Hyland K, Gropman A, Tierney E, Porter FD.

J Inherit Metab Dis. 2014 May;37(3):415-20. doi: 10.1007/s10545-013-9672-5. Epub 2014 Feb 6.

PubMed [citation]

PMID:: 24500076
PMCID:: PMC4166510

See all PubMed Citations (6)

Details of each submission

From OMIM, SCV000027387.2

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

Description

In 2 brothers with Smith-Lemli-Opitz syndrome (SLOS; 270400) described by Nowaczyk et al. (1998), Krakowiak et al. (2000) detected a C-to-T transition at nucleotide position 866 of the DHCR7 gene, resulting in a change from threonine to isoleucine at codon 289 (T289I). The T289I mutation occurs between the sixth and seventh transmembrane domain of the DHCR7 protein. This mutation was found in compound heterozygosity with the IVS8-1G-C mutation (602858.0001). Nowaczyk et al. (2001) extended study of these patients to their parents and female first cousin. The brothers' father carried the T289I missense mutation. The cousin, like the brothers, carried the IVS8-1G-C/T289I genotype.

#	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 Counsyl, SCV000486161.2

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

#	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, SCV001163698.1

#	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, SCV001203505.5

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

Description

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 289 of the DHCR7 protein (p.Thr289Ile). This variant is present in population databases (rs121909765, gnomAD 0.004%). This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 10995508, 11298379). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6789). 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

Last Updated: Sep 29, 2024

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