NM_152594.3(SPRED1):c.1151_1152del (p.Glu384fs) AND Legius syndrome

Clinical significance:Pathogenic (Last evaluated: Aug 17, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000226597.3

Allele description [Variation Report for NM_152594.3(SPRED1):c.1151_1152del (p.Glu384fs)]

NM_152594.3(SPRED1):c.1151_1152del (p.Glu384fs)

Gene:
SPRED1:sprouty related EVH1 domain containing 1 [Gene - OMIM - HGNC]
Variant type:
Microsatellite
Cytogenetic location:
15q14
Genomic location:
Preferred name:
NM_152594.3(SPRED1):c.1151_1152del (p.Glu384fs)
HGVS:
  • NC_000015.10:g.38351478AG[1]
  • NG_008980.1:g.103628AG[1]
  • NM_152594.3:c.1151_1152delMANE SELECT
  • NP_689807.1:p.Glu384fs
  • NC_000015.9:g.38643679AG[1]
  • NM_152594.2:c.1151_1152delAG
Protein change:
E384fs
Links:
dbSNP: rs878855228
NCBI 1000 Genomes Browser:
rs878855228
Molecular consequence:
  • NM_152594.3:c.1151_1152del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:
Legius syndrome (LGSS)
Synonyms:
Neurofibromatosis type 1 like syndrome
Identifiers:
MONDO: MONDO:0012669; MedGen: C1969623; Orphanet: 137605; OMIM: 611431

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000291521Invitaecriteria provided, single submitter
Pathogenic
(Aug 17, 2018)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Summary from all submissions

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

Citations

PubMed

Distinct requirements for the Sprouty domain for functional activity of Spred proteins.

King JA, Straffon AF, D'Abaco GM, Poon CL, I ST, Smith CM, Buchert M, Corcoran NM, Hall NE, Callus BA, Sarcevic B, Martin D, Lock P, Hovens CM.

Biochem J. 2005 Jun 1;388(Pt 2):445-54.

PubMed [citation]
PMID:
15683364
PMCID:
PMC1138951

Clinical and mutational spectrum of neurofibromatosis type 1-like syndrome.

Messiaen L, Yao S, Brems H, Callens T, Sathienkijkanchai A, Denayer E, Spencer E, Arn P, Babovic-Vuksanovic D, Bay C, Bobele G, Cohen BH, Escobar L, Eunpu D, Grebe T, Greenstein R, Hachen R, Irons M, Kronn D, Lemire E, Leppig K, Lim C, et al.

JAMA. 2009 Nov 18;302(19):2111-8. doi: 10.1001/jama.2009.1663. Erratum in: JAMA. 2010 Jun 23;303(24):2477.

PubMed [citation]
PMID:
19920235
See all PubMed Citations (6)

Details of each submission

From Invitae, SCV000291521.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This sequence change deletes 2 nucleotides from exon 7 of the SPRED1 mRNA (c.1151_1152delAG), causing a frameshift at codon 384 and creating a premature translational stop signal in the last exon of the SPRED1 mRNA (p.Glu384Glyfs*5). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the SPROUTY-related domain (SPR) responsible for translocation to the plasma membrane and interaction with the Raf protein. The SPR domain also mediates dimerization of Spred proteins (PMID: 15683364). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature. A different frameshift mutation c.1149_1152del (p.Gly385Ilefs*20) has been observed in several individuals and families with Legius syndrome (PMID: 19920235, 19443465, 21089071, 17704776), which suggests a truncation in the last exon disrupts SPRED1 function and causes disease. For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Oct 7, 2021

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