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NM_001360.3(DHCR7):c.546G>T (p.Trp182Cys) AND Smith-Lemli-Opitz syndrome

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Oct 5, 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:
RCV002867733.2

Allele description [Variation Report for NM_001360.3(DHCR7):c.546G>T (p.Trp182Cys)]

NM_001360.3(DHCR7):c.546G>T (p.Trp182Cys)

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.546G>T (p.Trp182Cys)
HGVS:
  • NC_000011.10:g.71441307C>A
  • NG_012655.2:g.12125G>T
  • NM_001163817.2:c.546G>T
  • NM_001360.3:c.546G>TMANE SELECT
  • NP_001157289.1:p.Trp182Cys
  • NP_001351.2:p.Trp182Cys
  • NP_001351.2:p.Trp182Cys
  • LRG_340t1:c.546G>T
  • LRG_340:g.12125G>T
  • LRG_340p1:p.Trp182Cys
  • NC_000011.9:g.71152353C>A
  • NM_001360.2:c.546G>T
Protein change:
W182C
Molecular consequence:
  • NM_001163817.2:c.546G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001360.3:c.546G>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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV003241286Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(Oct 5, 2022) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Novel mutations in the 7-dehydrocholesterol reductase gene of 13 patients with Smith--Lemli--Opitz syndrome.

Jira PE, Wanders RJ, Smeitink JA, De Jong J, Wevers RA, Oostheim W, Tuerlings JH, Hennekam RC, Sengers RC, Waterham HR.

Ann Hum Genet. 2001 May;65(Pt 3):229-36. doi: 10.1017/S0003480001008600.

PubMed [citation]
PMID:
11427181

Identification of 14 novel mutations in DHCR7 causing the Smith-Lemli-Opitz syndrome and delineation of the DHCR7 mutational spectra in Spain and Italy.

Witsch-Baumgartner M, Clayton P, Clusellas N, Haas D, Kelley RI, Krajewska-Walasek M, Lechner S, Rossi M, Zschocke J, Utermann G.

Hum Mutat. 2005 Apr;25(4):412.

PubMed [citation]
PMID:
15776424
See all PubMed Citations (5)

Details of each submission

From Invitae, SCV003241286.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Trp182 amino acid residue in DHCR7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11427181, 15776424, 15979035). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Studies have shown that this missense change alters DHCR7 gene expression (PMID: 10677299). 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. This missense change has been observed in individual(s) with clinical features of Smith–Lemli–Opitz syndrome (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 182 of the DHCR7 protein (p.Trp182Cys).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Feb 20, 2024