NM_005188.4(CBL):c.1259G>A (p.Arg420Gln) AND CBL-related disorder

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Jan 20, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001705593.15

Allele description [Variation Report for NM_005188.4(CBL):c.1259G>A (p.Arg420Gln)]

NM_005188.4(CBL):c.1259G>A (p.Arg420Gln)

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.1259G>A (p.Arg420Gln)

HGVS:

NC_000011.10:g.119278541G>A
NG_016808.1:g.77262G>A
NM_005188.4:c.1259G>AMANE SELECT
NP_005179.2:p.Arg420Gln
NP_005179.2:p.Arg420Gln
LRG_608t1:c.1259G>A
LRG_608:g.77262G>A
LRG_608p1:p.Arg420Gln
NC_000011.9:g.119149251G>A
NM_005188.2:c.1259G>A
NM_005188.3:c.1259G>A
NM_005188.4:c.1259G>A
P22681:p.Arg420Gln

Protein change:

R420Q; ARG420GLN

Links:

UniProtKB: P22681#VAR_064335; OMIM: 165360.0004; dbSNP: rs267606708

NCBI 1000 Genomes Browser:

rs267606708

Molecular consequence:

NM_005188.4:c.1259G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: CBL-related disorder
Synonyms:: Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia; CBL MUTATION-ASSOCIATED SYNDROME; CBL SYNDROME; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0013308; MedGen: C3150803; OMIM: 613563

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carcinoembryonic antigen-related cell adhesion molecule 19 isoform 2 precursor [...
carcinoembryonic antigen-related cell adhesion molecule 19 isoform 2 precursor [Homo sapiens]
gi|45267817|ref|NP_064604.2|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000035076	OMIM	no assertion criteria provided	Pathogenic (Aug 13, 2010)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001934399	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 26, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002061816	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 28, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005049298	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 20, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005364971	PreventionGenetics, part of Exact Sciences	no assertion criteria provided	Likely pathogenic (Jun 16, 2024)	germline	clinical testing

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Heterozygous germline mutations in the CBL tumor-suppressor gene cause a Noonan syndrome-like phenotype.

Martinelli S, De Luca A, Stellacci E, Rossi C, Checquolo S, Lepri F, Caputo V, Silvano M, Buscherini F, Consoli F, Ferrara G, Digilio MC, Cavaliere ML, van Hagen JM, Zampino G, van der Burgt I, Ferrero GB, Mazzanti L, Screpanti I, Yntema HG, Nillesen WM, Savarirayan R, et al.

Am J Hum Genet. 2010 Aug 13;87(2):250-7. doi: 10.1016/j.ajhg.2010.06.015. Epub 2010 Jul 8.

PubMed [citation]

PMID:: 20619386
PMCID:: PMC2917705

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From OMIM, SCV000035076.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001934399.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center, SCV002061816.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

PS3, PM2

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV005049298.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From PreventionGenetics, part of Exact Sciences, SCV005364971.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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