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

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Interpretation:
Pathogenic/Likely pathogenic​

Review status:
criteria provided, multiple submitters, no conflicts
Submissions:
7 (Most recent: Oct 22, 2021)
Last evaluated:
Oct 15, 2021
Accession:
VCV000177959.13
Variation ID:
177959
Description:
single nucleotide variant
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NM_005188.4(CBL):c.1228-2A>G

Allele ID
175345
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
11q23.3
Genomic location
11: 119149218 (GRCh37) GRCh37 UCSC
11: 119278508 (GRCh38) GRCh38 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NM_005188.3:c.1228-2A>G splice acceptor
NC_000011.10:g.119278508A>G
NC_000011.9:g.119149218A>G
... more HGVS
Protein change
-
Other names
IVS8AS, A-G, -2
Canonical SPDI
NC_000011.10:119278507:A:G
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
-
Links
ClinGen: CA181066
OMIM: 165360.0006
dbSNP: rs727504426
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Pathogenic/Likely pathogenic 2 criteria provided, multiple submitters, no conflicts Oct 23, 2020 RCV000220945.2
Likely pathogenic 1 criteria provided, single submitter Jun 4, 2014 RCV000154623.2
Pathogenic 1 criteria provided, single submitter Oct 15, 2021 RCV000157861.4
Pathogenic 1 criteria provided, single submitter Aug 21, 2019 RCV000705134.3
Likely pathogenic 1 criteria provided, single submitter Apr 4, 2017 RCV000722039.1
Pathogenic 1 no assertion criteria provided Sep 1, 2010 RCV001678585.1
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
CBL No evidence available No evidence available GRCh38
GRCh37
588 702

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Pathogenic
(Jun 04, 2014)
criteria provided, single submitter
Method: clinical testing
Juvenile myelomonocytic leukemia
(Somatic mutation)
Allele origin: somatic
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine
Accession: SCV000271340.2
Submitted: (Mar 21, 2019)
Evidence details
Publications
PubMed (4)
Comment:
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 … (more)
Likely pathogenic
(Jun 04, 2014)
criteria provided, single submitter
Method: clinical testing
Noonan syndrome
(Autosomal dominant inheritance)
Allele origin: germline
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine
Accession: SCV000204296.4
Submitted: (Mar 21, 2019)
Evidence details
Publications
PubMed (4)
Comment:
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 … (more)
Pathogenic
(Oct 15, 2021)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000207791.8
Submitted: (Oct 22, 2021)
Evidence details
Comment:
Previously reported as a homozygous variant in leukemia cells of several children with juvenile myelomonocytic leukemia (JMML), however, it is not clear if these patients … (more)
Likely pathogenic
(Apr 04, 2017)
criteria provided, single submitter
Method: clinical testing
Malignant germ cell tumor of ovary
Allele origin: germline
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital
Accession: SCV000853216.1
Submitted: (Aug 09, 2018)
Evidence details
Comment:
This is a splice site alteration in which an A is replaced by a G in intron 8, two nucleotides upstream from the beginning of … (more)
Likely pathogenic
(Oct 23, 2020)
criteria provided, single submitter
Method: clinical testing
Juvenile myelomonocytic leukemia
Allele origin: de novo
Baylor Genetics
Accession: SCV001523395.1
Submitted: (Feb 21, 2021)
Evidence details
Comment:
This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Pathogenic
(Aug 21, 2019)
criteria provided, single submitter
Method: clinical testing
Rasopathy
Allele origin: germline
Invitae
Accession: SCV000834117.3
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (3)
Comment:
This sequence change affects an acceptor splice site in intron 8 of the CBL gene. It is expected to disrupt RNA splicing and likely results … (more)
Pathogenic
(Sep 01, 2010)
no assertion criteria provided
Method: literature only
NOONAN SYNDROME-LIKE DISORDER WITH JUVENILE MYELOMONOCYTIC LEUKEMIA
Allele origin: germline
OMIM
Accession: SCV000043986.2
Submitted: (Jun 02, 2011)
Evidence details
Publications
PubMed (1)

Functional evidence

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There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Citations for this variant

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Title Author Journal Year Link
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Nykamp K Genetics in medicine : official journal of the American College of Medical Genetics 2017 PMID: 28492532
De novo mutations in CBL causing early-onset paediatric moyamoya angiopathy. Guey S Journal of medical genetics 2017 PMID: 28343148
Gene mutations in the Ras pathway and the prognostic implication in Korean patients with juvenile myelomonocytic leukemia. Park HD Annals of hematology 2012 PMID: 21901340
Genetic typing of CBL, ASXL1, RUNX1, TET2 and JAK2 in juvenile myelomonocytic leukaemia reveals a genetic profile distinct from chronic myelomonocytic leukaemia. Pérez B British journal of haematology 2010 PMID: 20955399
Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. Niemeyer CM Nature genetics 2010 PMID: 20694012
Mutations in CBL occur frequently in juvenile myelomonocytic leukemia. Loh ML Blood 2009 PMID: 19571318

Text-mined citations for rs727504426...

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These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 30, 2021