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NM_001360.3(DHCR7):c.1336C>T (p.Arg446Trp) AND Smith-Lemli-Opitz syndrome

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Jan 26, 2024
Review status:
criteria provided, conflicting classifications
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:
RCV000666265.8

Allele description [Variation Report for NM_001360.3(DHCR7):c.1336C>T (p.Arg446Trp)]

NM_001360.3(DHCR7):c.1336C>T (p.Arg446Trp)

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.1336C>T (p.Arg446Trp)
HGVS:
  • NC_000011.10:g.71435467G>A
  • NG_012655.2:g.17965C>T
  • NM_001163817.2:c.1336C>T
  • NM_001360.3:c.1336C>TMANE SELECT
  • NP_001157289.1:p.Arg446Trp
  • NP_001351.2:p.Arg446Trp
  • NP_001351.2:p.Arg446Trp
  • LRG_340t1:c.1336C>T
  • LRG_340:g.17965C>T
  • LRG_340p1:p.Arg446Trp
  • NC_000011.9:g.71146513G>A
  • NM_001360.2:c.1336C>T
Protein change:
R446W
Links:
dbSNP: rs145043679
NCBI 1000 Genomes Browser:
rs145043679
Molecular consequence:
  • NM_001163817.2:c.1336C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001360.3:c.1336C>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
SCV000790527Counsyl
criteria provided, single submitter

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))		Uncertain significance
(Mar 28, 2017) 		unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV002265694Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(Jan 26, 2024) 		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
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Mutational spectrum of Smith-Lemli-Opitz syndrome.

Waterham HR, Hennekam RC.

Am J Med Genet C Semin Med Genet. 2012 Nov 15;160C(4):263-84. doi: 10.1002/ajmg.c.31346. Epub 2012 Oct 5. Review.

PubMed [citation]
PMID:
23042628

Mutational spectrum in the Delta7-sterol reductase gene and genotype-phenotype correlation in 84 patients with Smith-Lemli-Opitz syndrome.

Witsch-Baumgartner M, Fitzky BU, Ogorelkova M, Kraft HG, Moebius FF, Glossmann H, Seedorf U, Gillessen-Kaesbach G, Hoffmann GF, Clayton P, Kelley RI, Utermann G.

Am J Hum Genet. 2000 Feb;66(2):402-12.

PubMed [citation]
PMID:
10677299
PMCID:
PMC1288092
See all PubMed Citations (6)

Details of each submission

From Counsyl, SCV000790527.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002265694.3

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

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 446 of the DHCR7 protein (p.Arg446Trp). This variant is present in population databases (rs145043679, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with DHCR7-related conditions. ClinVar contains an entry for this variant (Variation ID: 551257). 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.Arg446 amino acid residue in DHCR7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10677299, 12270273, 12818773, 27513191). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

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

Last Updated: Sep 29, 2024