ClinVar Genomic variation as it relates to human health
NM_005188.4(CBL):c.1259G>A (p.Arg420Gln)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_005188.4(CBL):c.1259G>A (p.Arg420Gln)
Variation ID: 13810 Accession: VCV000013810.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q23.3 11: 119278541 (GRCh38) [ NCBI UCSC ] 11: 119149251 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jan 9, 2017 Nov 24, 2024 Oct 8, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005188.4:c.1259G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005179.2:p.Arg420Gln missense NC_000011.10:g.119278541G>A NC_000011.9:g.119149251G>A NG_016808.1:g.77262G>A LRG_608:g.77262G>A LRG_608t1:c.1259G>A LRG_608p1:p.Arg420Gln P22681:p.Arg420Gln - Protein change
- R420Q
- Other names
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- Canonical SPDI
- NC_000011.10:119278540:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00002
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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CBL | No evidence available | No evidence available |
GRCh38 GRCh37 |
1456 | 1611 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jul 21, 2023 | RCV000414703.14 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 12, 2023 | RCV000816470.15 | |
Pathogenic (1) |
no assertion criteria provided
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Sep 1, 2020 | RCV001257538.8 | |
Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Oct 8, 2024 | RCV001705593.16 | |
Likely pathogenic (1) |
no assertion criteria provided
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- | RCV003447475.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 20, 2024 | RCV004558248.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Nov 12, 2023)
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criteria provided, single submitter
Method: clinical testing
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RASopathy
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000956980.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 420 of the CBL protein (p.Arg420Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 420 of the CBL protein (p.Arg420Gln). This variant is present in population databases (rs267606708, gnomAD no frequency). This missense change has been observed in individuals with clinical features of Noonan syndrome (PMID: 20619386, 33318624). ClinVar contains an entry for this variant (Variation ID: 13810). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CBL protein function. Experimental studies have shown that this missense change affects CBL function (PMID: 17446348, 20619386, 22246246, 25178484, 33627783). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 20, 2024)
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criteria provided, single submitter
Method: clinical testing
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CBL-related disorder
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV005049298.1
First in ClinVar: Jun 09, 2024 Last updated: Jun 09, 2024 |
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Pathogenic
(Jan 20, 2024)
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criteria provided, single submitter
Method: clinical testing
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Juvenile myelomonocytic leukemia
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV005049413.1
First in ClinVar: Jun 09, 2024 Last updated: Jun 09, 2024 |
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Likely pathogenic
(Jan 26, 2021)
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criteria provided, single submitter
Method: clinical testing
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CBL-related disorder
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001934399.1
First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021 |
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Likely pathogenic
(Dec 28, 2021)
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criteria provided, single submitter
Method: clinical testing
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CBL-related disorder
Affected status: yes
Allele origin:
germline
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Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV002061816.2
First in ClinVar: Jan 22, 2022 Last updated: Feb 11, 2022 |
Comment:
PS3, PM2
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Pathogenic
(Mar 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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RASopathy
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003922954.1
First in ClinVar: May 13, 2023 Last updated: May 13, 2023 |
Comment:
Variant summary: CBL c.1259G>A (p.Arg420Gln) results in a conservative amino acid change to a highly conserved residue (HGMD) located in the RING-type Zinc finger (IPR001841) … (more)
Variant summary: CBL c.1259G>A (p.Arg420Gln) results in a conservative amino acid change to a highly conserved residue (HGMD) located in the RING-type Zinc finger (IPR001841) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251418 control chromosomes. c.1259G>A has been reported in the literature in individuals affected with Noonan Syndrome And Related Conditions (e.g. Digilio_2010, Kauffmann_2021, Martinelli_2010). These data indicate that the variant is likely to be associated with disease. At least three publications report experimental evidence evaluating an impact on protein function, finding that the variant inhibits CBL ubiquitin ligase function and EGFR trafficking (Sargin_2007, Martinelli_2010, Brand_2014). Seven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic/likely pathogenic (n=6) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jul 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000491156.6
First in ClinVar: Jan 09, 2017 Last updated: Jul 29, 2023 |
Comment:
Functional studies demonstrate that R420Q impairs epidermal growth factor receptor (EGFR) ubiquitylation and degredation, and the R420Q-containing RING domain is not able to function as … (more)
Functional studies demonstrate that R420Q impairs epidermal growth factor receptor (EGFR) ubiquitylation and degredation, and the R420Q-containing RING domain is not able to function as an E3 ubiquitin ligase (PMID: 25178484, 17446348); This variant is associated with the following publications: (PMID: 19734451, 24803665, 17446348, 21768087, 20619386, 25952305, 32054657, 31751678, 32855275, 34026204, 35033063, 33627783, 33512474, 35967575, 22246246, 35008940, 33318624, 33372952, 34906245, 35583390, 25178484, 22315494) (less)
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Likely pathogenic
(Dec 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003824973.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Likely pathogenic
(Oct 08, 2024)
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criteria provided, single submitter
Method: clinical testing
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CBL-related disorder
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV005398926.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0105 - The mechanism of disease for this … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However, dominant negative is a likely mechanism of disease (PMID: 20619386, 20694012). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Germline CBL pathogenic variants are associated with phenotypic heterogeneity and variable expressivity (PMID: 25952305). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (3 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. Pathogenic variants cluster in the linker region and RING finger domain (PMID: 25952305). (SP) 0710 - Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. p.(Arg420Leu) and p.(Arg420Pro) have both been once classified as a variant of unknown significance in ClinVar. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic/likely pathogenic six times in ClinVar, and has been reported in the literature in an individual diagnosed with Noonan syndrome-like disorder (PMID: 20619386, 22190897). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. p.(Arg420Gln) mutants were expressed in vitro. Compared to wild-type cells, mutants showed impaired EGFR ubiquitylation and increased RAS-MAPK signalling (PMID: 20619389, 25178484). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Aug 13, 2010)
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no assertion criteria provided
Method: literature only
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NOONAN SYNDROME-LIKE DISORDER WITHOUT JUVENILE MYELOMONOCYTIC LEUKEMIA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000035076.2
First in ClinVar: Apr 04, 2013 Last updated: May 01, 2017 |
Comment on evidence:
In a father and daughter with Noonan syndrome-like disorder (NSLL; 613563), Martinelli et al. (2010) identified a heterozygous 1259G-A transition in the CBL gene, resulting … (more)
In a father and daughter with Noonan syndrome-like disorder (NSLL; 613563), Martinelli et al. (2010) identified a heterozygous 1259G-A transition in the CBL gene, resulting in an arg420-to-gln (R420Q) substitution in the RING finger domain. The R420Q mutation was not detected in 400 population-matched controls. In vitro functional expression studies showed that the mutation caused impaired CBL-mediated degradation of cell-surface receptors in a dominant-negative fashion. These results were compatible with dysregulated intracellular signaling through RAS. (less)
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Likely pathogenic
(-)
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no assertion criteria provided
Method: provider interpretation
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Myeloproliferative disorder
Affected status: yes
Allele origin:
germline
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Molecular Diagnostics Laboratory, University of Rochester Medical Center
Accession: SCV004175185.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Age: 70-79 years
Sex: female
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Pathogenic
(Sep 01, 2020)
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no assertion criteria provided
Method: provider interpretation
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Rhabdomyosarcoma
Affected status: yes
Allele origin:
germline
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Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV001434364.1
First in ClinVar: Oct 02, 2020 Last updated: Oct 02, 2020 |
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Likely pathogenic
(Jun 16, 2024)
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no assertion criteria provided
Method: clinical testing
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CBL-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV005364971.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The CBL c.1259G>A variant is predicted to result in the amino acid substitution p.Arg420Gln. This variant has been reported in an individual with acute myeloid … (more)
The CBL c.1259G>A variant is predicted to result in the amino acid substitution p.Arg420Gln. This variant has been reported in an individual with acute myeloid leukemia (AML) (Sargin et al. 2007. PubMed ID: 17446348), and in a family with Noonan syndrome-like phenotype (Martinelli et al. 2010. PubMed ID: 20619386). This variant alters the conserved residue located in the RING finger domain which is a known mutational hot spot in myeloid malignancies. Functional studies showed that this variant causes aberrant ubiquitylation and trafficking of EGFR (Martinelli et al. 2010. PubMed ID: 20619386; Brand et al. 2014. PubMed ID: 25178484; Kiel et al. 2014. PubMed ID: 24803665). This variant is reported in 0.0028% of alleles in individuals of Latino descent in gnomAD. In summary, this variant is interpreted as likely pathogenic. (less)
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Germline Functional Evidence
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 germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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E3 ligase-inactivation rewires CBL interactome to elicit oncogenesis by hijacking RTK-CBL-CIN85 axis. | Ahmed SF | Oncogene | 2021 | PMID: 33627783 |
Germline Cancer Predisposition Variants in Pediatric Rhabdomyosarcoma: A Report From the Children's Oncology Group. | Li H | Journal of the National Cancer Institute | 2021 | PMID: 33372952 |
Genotype-phenotype association by echocardiography offers incremental value in patients with Noonan Syndrome with Multiple Lentigines. | Kauffman H | Pediatric research | 2021 | PMID: 33318624 |
Impact of genomic alterations on outcomes in myelofibrosis patients undergoing JAK1/2 inhibitor therapy. | Spiegel JY | Blood advances | 2017 | PMID: 29296819 |
The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. | Arber DA | Blood | 2016 | PMID: 27069254 |
Molecular Diversity and Associated Phenotypic Spectrum of Germline CBL Mutations. | Martinelli S | Human mutation | 2015 | PMID: 25952305 |
TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients. | Bejar R | Blood | 2014 | PMID: 25224413 |
RASopathy-associated CBL germline mutations cause aberrant ubiquitylation and trafficking of EGFR. | Brand K | Human mutation | 2014 | PMID: 25178484 |
Prognostic score including gene mutations in chronic myelomonocytic leukemia. | Itzykson R | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2013 | PMID: 23690417 |
Activating CBL mutations are associated with a distinct MDS/MPN phenotype. | Schwaab J | Annals of hematology | 2012 | PMID: 23010802 |
Use of CBL exon 8 and 9 mutations in diagnosis of myeloproliferative neoplasms and myelodysplastic/myeloproliferative disorders: an analysis of 636 cases. | Schnittger S | Haematologica | 2012 | PMID: 22733026 |
CBL mutation-related patterns of phosphorylation and sensitivity to tyrosine kinase inhibitors. | Makishima H | Leukemia | 2012 | PMID: 22246246 |
RASopathies: Clinical Diagnosis in the First Year of Life. | Digilio MC | Molecular syndromology | 2011 | PMID: 22190897 |
Mutational spectrum analysis of chronic myelomonocytic leukemia includes genes associated with epigenetic regulation: UTX, EZH2, and DNMT3A. | Jankowska AM | Blood | 2011 | PMID: 21828135 |
Does bilateral salpingectomy with ovarian retention warrant consideration as a temporary bridge to risk-reducing bilateral oophorectomy in BRCA1/2 mutation carriers? | Greene MH | American journal of obstetrics and gynecology | 2011 | PMID: 20619389 |
Myeloid leukemia development in c-Cbl RING finger mutant mice is dependent on FLT3 signaling. | Rathinam C | Cancer cell | 2010 | PMID: 20951944 |
Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. | Niemeyer CM | Nature genetics | 2010 | PMID: 20694012 |
Heterozygous germline mutations in the CBL tumor-suppressor gene cause a Noonan syndrome-like phenotype. | Martinelli S | American journal of human genetics | 2010 | PMID: 20619386 |
Mutations of e3 ubiquitin ligase cbl family members constitute a novel common pathogenic lesion in myeloid malignancies. | Makishima H | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2009 | PMID: 19901108 |
Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms. | Sanada M | Nature | 2009 | PMID: 19620960 |
Frequent CBL mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms. | Grand FH | Blood | 2009 | PMID: 19387008 |
Flt3-dependent transformation by inactivating c-Cbl mutations in AML. | Sargin B | Blood | 2007 | PMID: 17446348 |
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Text-mined citations for rs267606708 ...
HelpRecord last updated Nov 25, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.