NM_005188.4(CBL):c.1228-2A>G AND Noonan syndrome

Clinical significance:Likely pathogenic (Last evaluated: Jun 4, 2014)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000154623.2

Allele description [Variation Report for NM_005188.4(CBL):c.1228-2A>G]

NM_005188.4(CBL):c.1228-2A>G

Gene:
CBL:Cbl proto-oncogene [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
11q23.3
Genomic location:
Preferred name:
NM_005188.4(CBL):c.1228-2A>G
HGVS:
  • NC_000011.10:g.119278508A>G
  • NG_016808.1:g.77229A>G
  • NM_005188.3:c.1228-2A>G
  • NM_005188.4:c.1228-2A>GMANE SELECT
  • LRG_608t1:c.1228-2A>G
  • LRG_608:g.77229A>G
  • NC_000011.9:g.119149218A>G
  • NM_005188.2:c.1228-2A>G
Nucleotide change:
IVS8AS, A-G, -2
Links:
OMIM: 165360.0006; dbSNP: rs727504426
NCBI 1000 Genomes Browser:
rs727504426
Molecular consequence:
  • NM_005188.3:c.1228-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_005188.4:c.1228-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
Observations:
1

Condition(s)

Name:
Noonan syndrome (NS)
Synonyms:
Noonan's syndrome; Pseudo-Turner syndrome
Identifiers:
MONDO: MONDO:0018997; MeSH: D009634; MedGen: C0028326; OMIM: PS163950

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000204296Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
Likely pathogenic
(Jun 4, 2014)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot provided11not providednot providednot providedclinical testing

Citations

PubMed

Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia.

Niemeyer CM, Kang MW, Shin DH, Furlan I, Erlacher M, Bunin NJ, Bunda S, Finklestein JZ, Gorr TA, Mehta P, Schmid I, Kropshofer G, Corbacioglu S, Lang PJ, Klein C, Schlegel PG, Heinzmann A, Schneider M, StarĂ½ J, van den Heuvel-Eibrink MM, Hasle H, Locatelli F, et al.

Nat Genet. 2010 Sep;42(9):794-800. doi: 10.1038/ng.641. Epub 2010 Aug 8.

PubMed [citation]
PMID:
20694012
PMCID:
PMC4297285

Mutations in CBL occur frequently in juvenile myelomonocytic leukemia.

Loh ML, Sakai DS, Flotho C, Kang M, Fliegauf M, Archambeault S, Mullighan CG, Chen L, Bergstraesser E, Bueso-Ramos CE, Emanuel PD, Hasle H, Issa JP, van den Heuvel-Eibrink MM, Locatelli F, Stary J, Trebo M, Wlodarski M, Zecca M, Shannon KM, Niemeyer CM.

Blood. 2009 Aug 27;114(9):1859-63. doi: 10.1182/blood-2009-01-198416. Epub 2009 Jul 1.

PubMed [citation]
PMID:
19571318
PMCID:
PMC2738571
See all PubMed Citations (5)

Details of each submission

From Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, SCV000204296.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (5)

Description

The 1228-2A>G variant in CBL has previously been identified in 5 individuals wit h juvenile myelomonocytic leukemia (JMML; Niemeyer 2010, Perez 2010, Park 2012, Loh 2009), in each of whom it was identified in the homozygous state in the leuk emia cells. At least one of these individuals also had clinical features of a No onan spectrum disorder, and this variant was not identified in either parent of this individual and likely occurred de novo (Niemeyer 2010). In addition, this v ariant was absent from large population studies. Studies have shown that the 122 8-2A>G variant is leads to deletion of exon 9 and is predicted to encode a prote in that lacks essential regions of the linker and RING finger domains (Niemeyer 2010). In summary, this variant is likely to be pathogenic, though additional st udies are required to fully establish its clinical significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided1not provided1not provided

Last Updated: Oct 30, 2021

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