rs267606708

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3_ModeratePP5_Very_Strong

The NM_005188.4(CBL):c.1259G>A(p.Arg420Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,614,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

CBL
NM_005188.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 9.60

Variant links:

Genes affected

CBL (HGNC:1541): (Cbl proto-oncogene) This gene is a proto-oncogene that encodes a RING finger E3 ubiquitin ligase. The encoded protein is one of the enzymes required for targeting substrates for degradation by the proteasome. This protein mediates the transfer of ubiquitin from ubiquitin conjugating enzymes (E2) to specific substrates. This protein also contains an N-terminal phosphotyrosine binding domain that allows it to interact with numerous tyrosine-phosphorylated substrates and target them for proteasome degradation. As such it functions as a negative regulator of many signal transduction pathways. This gene has been found to be mutated or translocated in many cancers including acute myeloid leukaemia, and expansion of CGG repeats in the 5' UTR has been associated with Jacobsen syndrome. Mutations in this gene are also the cause of Noonan syndrome-like disorder. [provided by RefSeq, Jul 2016]

CBL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.876

PP5

Variant 11-119278541-G-A is Pathogenic according to our data. Variant chr11-119278541-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-119278541-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBL	NM_005188.4 link	c.1259G>A	p.Arg420Gln	missense_variant	Exon 9 of 16	ENST00000264033.6	NP_005179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBL	ENST00000264033.6 link	c.1259G>A	p.Arg420Gln	missense_variant	Exon 9 of 16	1	NM_005188.4	ENSP00000264033.3		P22681

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251418

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1461828

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000143

Hom.:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

CBL-related disorder

Pathogenic:6

Jan 20, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 26, 2021

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 16, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Aug 13, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 08, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Dec 28, 2021

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PM2 -

not provided

Pathogenic:3

Apr 24, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CBL c.1259G>A; p.Arg420Gln variant (rs267606708) is reported in the literature in at least four individuals affected with Noonan syndrome-like disorders (Kauffman 2021, Martinelli 2010). This variant is also reported in ClinVar (Variation ID: 13810). This variant is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. In vitro functional analyses demonstrate that this mutation disrupts CBL ubiquitin ligase activity and trafficking of EGFR (Brand 2014, Martinelli 2010). Computational analyses predict that this variant is deleterious (REVEL: 0.858). Based on available information, this variant is considered to be likely pathogenic. References: Brand K et al. RASopathy-associated CBL germline mutations cause aberrant ubiquitylation and trafficking of EGFR. Hum Mutat. 2014 Nov. PMID: 25178484. Kauffman H et al. Genotype-phenotype association by echocardiography offers incremental value in patients with Noonan Syndrome with Multiple Lentigines. Pediatr Res. 2021 Aug. PMID: 33318624. Martinelli S et al. Heterozygous germline mutations in the CBL tumor-suppressor gene cause a Noonan syndrome-like phenotype. Am J Hum Genet. 2010 Aug 13. PMID: 20619386. -

Dec 06, 2021

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 21, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

RASopathy

Pathogenic:2

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CBL protein function with a positive predictive value of 95%. 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. -

Mar 07, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Myeloproliferative disorder

Pathogenic:1

Molecular Diagnostics Laboratory, University of Rochester Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

- -

Rhabdomyosarcoma

Pathogenic:1

Sep 01, 2020

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

- -

Juvenile myelomonocytic leukemia

Pathogenic:1

Jan 20, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

D;.;D;.

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.97

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D;D;D

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.88

D;D;D;D

MetaSVM

Uncertain

0.57

MutationAssessor

Uncertain

2.4

M;.;.;.

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-3.5

D;.;.;.

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

D;.;.;.

Sift4G

Uncertain

0.0030

D;D;D;.

Polyphen

1.0

D;.;.;.

Vest4

0.97

MVP

0.97

MPC

0.82

ClinPred

0.98

GERP RS

6.0

Varity_R

0.99

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over