11-119278181-T-C

Position:

chr11-119278181-T-C

Variant summary

Our verdict is Pathogenic. Variant got 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. Y371N) has been classified as 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 criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 7.67

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 18 ACMG points.

PM1

In a region_of_interest Linker (size 28) in uniprot entity CBL_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) 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-A is described in Lovd as [Pathogenic].

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 id is 13811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-119278181-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CBL	NM_005188.4 linkuse as main transcript	c.1111T>C	p.Tyr371His	missense_variant	8/16	ENST00000264033.6	NP_005179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CBL	ENST00000264033.6 linkuse as main transcript	c.1111T>C	p.Tyr371His	missense_variant	8/16	1	NM_005188.4	ENSP00000264033.3		P22681

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

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250954

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135658

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 SAS 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

Gnomad4 AFR exome

AF:

0.0000301

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000182

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00000994

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 02, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 21, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 28, 2021	PP1, PP3, PM1, PS2, PS3, PS4_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 02, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Feb 14, 2017	- -

CBL-related disorder

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	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 -
Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Jun 20, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	Dec 27, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Aug 16, 2023	PS2, PS3, PM1, PP3 -

Juvenile myelomonocytic leukemia;C3150803:CBL-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Dec 30, 2019

[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

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2010

- -

See cases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Jul 08, 2022

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

Juvenile myelomonocytic leukemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

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. -

RASopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 14, 2023

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). 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) performed at Invitae 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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.96

D;.;D;.

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D;D

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.96

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.7

M;.;.;.

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-4.7

D;.;.;.

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;.;.;.

Sift4G

Pathogenic

0.0

D;D;D;.

Polyphen

1.0

D;.;.;.

Vest4

0.98

MutPred

0.89

Gain of disorder (P = 0.0374);Gain of disorder (P = 0.0374);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

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