NM_001360.3(DHCR7):c.98+2_98+6del AND Smith-Lemli-Opitz syndrome

Clinical significance:Likely pathogenic (Last evaluated: Apr 20, 2021)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV001235655.3

Allele description [Variation Report for NM_001360.3(DHCR7):c.98+2_98+6del]

NM_001360.3(DHCR7):c.98+2_98+6del

Gene:
DHCR7:7-dehydrocholesterol reductase [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
11q13.4
Genomic location:
Preferred name:
NM_001360.3(DHCR7):c.98+2_98+6del
HGVS:
  • NC_000011.10:g.71444849_71444853del
  • NC_000011.10:g.71444851_71444855del
  • NG_012655.2:g.8579_8583del
  • NM_001163817.2:c.98+2_98+6del
  • NM_001360.3:c.98+2_98+6delMANE SELECT
  • LRG_340t1:c.98+2_98+6del
  • LRG_340:g.8579_8583del
  • NC_000011.9:g.71155895_71155899del
  • NC_000011.9:g.71155897_71155901del
  • NM_001360.2:c.98+2_98+6del
  • NM_001360.2:c.98+2_98+6delTAAGG
Links:
Molecular consequence:
  • NM_001163817.2:c.98+2_98+6del - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001360.3:c.98+2_98+6del - splice donor variant - [Sequence Ontology: SO:0001575]

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

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001408349Invitaecriteria provided, single submitter
Likely pathogenic
(Sep 20, 2019)
germlineclinical testing

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

SCV001623357Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely pathogenic
(Apr 20, 2021)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

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

Citations

PubMed

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]
PMID:
16199547
PMCID:
PMC1735933

Mutations in the human sterol delta7-reductase gene at 11q12-13 cause Smith-Lemli-Opitz syndrome.

Wassif CA, Maslen C, Kachilele-Linjewile S, Lin D, Linck LM, Connor WE, Steiner RD, Porter FD.

Am J Hum Genet. 1998 Jul;63(1):55-62.

PubMed [citation]
PMID:
9634533
PMCID:
PMC1377256
See all PubMed Citations (6)

Details of each submission

From Invitae, SCV001408349.2

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

Description

This sequence change affects a donor splice site in intron 3 of the DHCR7 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with Smith–Lemli–Opitz syndrome (PMID: 23042628). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DHCR7 are known to be pathogenic (PMID: 9634533, 10677299). 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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001623357.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

Variant summary: DHCR7 c.98+2_98+6delTAAGG is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251496 control chromosomes. c.98+2_98+6delTAAGG has been reported in the literature in at-least one individual affected with Smith-Lemli-Opitz Syndrome and has been subsequently cited by others (example, Waterham_2012, Bianconi_2015). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic citing an overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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

Last Updated: Jun 14, 2021

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