NM_005188.4:c.1111T>C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_005188.4(CBL):c.1111T>C(p.Tyr371His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000025 in 1,602,246 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y371D) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CBL
NM_005188.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18

Conservation

PhyloP100: 7.67

Publications

74 publications found

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 Gene-Disease associations (from GenCC):

CBL-related disorder
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, Genomics England PanelApp
juvenile myelomonocytic leukemia
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Noonan syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CBL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 19 uncertain in NM_005188.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-119278181-T-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2137268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.964

PP5

Variant 11-119278181-T-C is Pathogenic according to our data. Variant chr11-119278181-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 13811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005188.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBL	NM_005188.4	MANE Select	c.1111T>C	p.Tyr371His	missense	Exon 8 of 16	NP_005179.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CBL	ENST00000264033.6	TSL:1 MANE Select	c.1111T>C	p.Tyr371His	missense	Exon 8 of 16	ENSP00000264033.3
CBL	ENST00000634586.1	TSL:5	c.1111T>C	p.Tyr371His	missense	Exon 8 of 18	ENSP00000489218.1
CBL	ENST00000637974.1	TSL:5	c.1105T>C	p.Tyr369His	missense	Exon 8 of 17	ENSP00000490763.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000797

AC:

AN:

250954

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000207

AC:

AN:

1450020

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

722296

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000301

AC:

AN:

33238

American (AMR)

AF:

0.00

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26064

East Asian (EAS)

AF:

0.00

AC:

AN:

39642

South Asian (SAS)

AF:

0.00

AC:

AN:

86018

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00000182

AC:

AN:

1101236

Other (OTH)

AF:

0.00

AC:

AN:

59950

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00846340), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.358

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74358

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41460

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000192

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00000664

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Aug 02, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect (Niemeyer et al., 2010; Javadi et al., 2013).; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 20543203, 25952305, 27609087, 25283271, 19571318, 20694012, 23696637, 24803665, 27577878, 26911351, 28082680, 26676746, 28414188, 32933826, 20619386, 22315494)

Feb 14, 2017

Blueprint Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 21, 2022

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 28, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP1, PP3, PM1, PS2, PS3, PS4_moderate

Nov 02, 2022

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CBL c.1111T>C (p.Tyr371His) missense variant results in the substitution of tyrosine at amino acid 371 with histidine. Across a selection of the available literature, this variant has been identified in a heterozygous state in at least 13 individuals with Noonan syndrome-like disorder with or without juvenile monomyelocytic leukemia, including six individuals in which the variant was de novo (PMID: 20543203; PMID: 20694012; PMID: 25283271; PMID: 25952305). There are several instances in which the variant was inherited from a parent, however detailed phenotype is not provided (PMID: 20543203; PMID: 20694012). At least three other missense variants at the same residue have been reported in individuals with the condition (PMID: 20694012). The reported frequency of this allele in the Genome Aggregation Database is 0.000011 in the total population (version 2.1.1). Functional studies have demonstrated a gain-of-function effect for the c.1111T>C variant (PMID: 20694012). Based on the available evidence, the c.1111T>C (p.Tyr371His) variant is classified as pathogenic for Noonan syndrome-like disorder with or without juvenile monomyelocytic leukemia.

Aug 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CBL: PM6:Very Strong, PS4, PM1, PM2, PM5, PP3, PS3:Supporting

CBL-related disorder

Pathogenic:5

Jun 14, 2024

3billion

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v4.0.0 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.97 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.91 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013811 /PMID: 19571318). Different missense changes at the same codon (p.Tyr371Asn, p.Tyr371Asp, p.Tyr371Cys, p.Tyr371Phe, p.Tyr371Ser) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000029824, VCV000180827, VCV000548022, VCV000949693, VCV002137268 /PMID: 19571318, 28343148). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

Jun 20, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The CBL c.1111T>C variant is predicted to result in the amino acid substitution p.Tyr371His. This variant has been reported as a heterozygous germline variant in patients with juvenile myelomonocytic leukemia (JMML) (Pathak et al. 2015. PubMed ID: 25939664), in patients with Noonan syndrome-like disorder with or without JMML (Perez et al. 2010. PubMed ID: 20543203; Neimeyer et al. 2010. PubMed ID: 20694012), and in unaffected family members of patients with JMML (Perez et al. 2010. PubMed ID: 20543203; Pathak et al. 2015. PubMed ID: 25939664), suggesting that this variant is incompletely penetrant. In patients with JMML, analysis of leukemia cells showed a somatically acquired loss of heterozygosity of chromosome 11q23, containing the CBL (Loh et al. 2009. PubMed ID: 19571318; Perez et al. 2010. PubMed ID: 20543203). This variant is reported in 0.0050% of alleles in individuals of East Asian descent in gnomAD. In addition, other missense variants at this same amino acid have also been reported as pathogenic (p.Tyr371Asp, p.Tyr371Cys, p.Tyr371Asn, and p.Tyr371Ser) (Loh et al. 2009. PubMed ID: 19571318). Based on this evidence, we interpret this variant as pathogenic.

Aug 16, 2023

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS2, PS3, PM1, PP3

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: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 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 pathogenic CBL variants are associated with variable phenotype (PMID: 25952305). (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to histidine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (3 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a moderate amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants, adjacent to the Prok-RING 4 domain (DECIPHER; PMIDs: 25358541, 25952305). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical diagnostic laboratories (ClinVar). It has been reported in multiple individuals with Noonan syndrome or Noonan-like features with or without haematology anomalies. and confirmed to be de novo in the several probands (PMIDs: 25283271, 25952305, 28414188). In addition, this variant has been shown to be heterozygous in the germline tissue and homozygous in the somatic tissue (reviewed by PMID: 25952305). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Dec 27, 2023

Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Juvenile myelomonocytic leukemia

Pathogenic:2

Sep 15, 2025

Department of Molecular Genetics, Istishari Arab Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CBL variant c.1111T>C, p.Tyr371His creates an amino acid change from Tyr to His at position 371. This variant has been previously reported in patients with Noonan syndrome-like disorder and onset of juvenile myelomonocytic leukemia (JMML) (PMID: 20543203, 19571318, 20694012). Perez et al. (2010) reported that Leukemic cells from all patients showed AOH at chromosome 11q23, including the CBL gene. The patients all demonstrated subtle developmental defects, including dysmorphic facial features and poor growth, and 1 patient had developmental delay. It is classified as pathogenic based on ACMG/AMP/ClinGen SVI guidelines. Although the condition is typically inherited in an autosomal dominant manner, the homozygosity in this patient is likely explained by a large AOH region encompassing CBL on chromosome 11q.

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces tyrosine with histidine at codon 371 of the CBL protein (p.Tyr371His). The tyrosine residue is highly conserved (PhyloP=7.65) .This variant is not present in population databases (GnomAD). This variant has been reported with CBL-Related Disorder, Hematopoietic and Lymphoid Cell Neoplasm and Hematopoietic and Lymphoid System Neoplasm in the following publications: (PMID: 20543203, 25952305, 27609087, 25283271, 19571318, 20694012, 23696637, 24803665, 27577878, 26911351, 28082680, 26676746, 28414188, 32933826). ClinVar contains an entry for this variant (Variation ID: 13811) from seven clinical lab after 2014 and all labs were classified this variant as pathogenic.

Juvenile myelomonocytic leukemia;C3150803:CBL-related disorder

Pathogenic:1

Dec 30, 2019

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

[ACMG/AMP: PS2, PS3, PM1, PP3] This alteration is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) [PS2], is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3], is located in a mutational hotspot and/or critical and well-established functional domain [PM1], is predicted to be damaging by multiple functional prediction tools [PP3].

Noonan syndrome-like disorder with juvenile myelomonocytic leukemia

Pathogenic:1

Oct 01, 2010

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

See cases

Pathogenic:1

Jul 08, 2022

Institute of Human Genetics, University Hospital Muenster

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG categories: PS3,PM1,PM2,PP3,PP5

Cardiovascular phenotype

Pathogenic:1

Jul 18, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1111T>C (p.Y371H) alteration is located in exon 8 (coding exon 8) of the CBL gene. This alteration results from a T to C substitution at nucleotide position 1111, causing the tyrosine (Y) at amino acid position 371 to be replaced by a histidine (H). Based on data from gnomAD, the C allele has an overall frequency of 0.001% (3/282362) total alleles studied. The highest observed frequency was 0.005% (1/19950) of East Asian alleles. This variant was reported in individuals with features consistent with CBL-related RASopathy; in multiple individuals, it was determined to be de novo (Loh, 2009; Niemeyer, 2010; Pérez, 2010; Hyakuna, 2015; Martinelli, 2015; Coe, 2017). This amino acid position is highly conserved in available vertebrate species. In multiple assays testing CBL function, this variant showed functionally abnormal results (Niemeyer, 2010). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

RASopathy

Pathogenic:1

Oct 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 371 of the CBL protein (p.Tyr371His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with juvenile myelomonocytic leukemia and Noonan-like syndrome (PMID: 20543203, 20694012, 25283271, 25952305, 28414188). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13811). 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: 20694012, 23696637). For these reasons, this variant has been classified as Pathogenic.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.96

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.96

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.7

PhyloP100

7.7

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-4.7

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.98

MutPred

0.89

Gain of disorder (P = 0.0374)

MVP

0.99

MPC

0.89

ClinPred

0.98

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.90

gMVP

0.70

Mutation Taster

=12/88

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over