Gene Validity Curation

CBL - Noonan syndrome-like disorder with juvenile myelomonocytic leukemia

Gene: CBL (HGNC:1541)
Classification - 04/29/2019
Disease: Noonan syndrome-like disorder with juvenile myelomonocytic leukemia (MONDO_0013308)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: RASopathy EP
Evidence Summary: CBL was first reported in relation to autosomal dominant CBL-related disorders in 2010 (Martinelli et al., PMID 20619386). At least 9 variants (e.g. missense, splice site) have been reported in humans. Evidence supporting this gene-disease relationship includes case level data and experimental data including a functional alteration study expressing patient variants in heterologous cell lines and two different mouse models (PMIDs 20619386, 28082680, 28209720, 20951944). CBL-related disorder is a genetic condition caused by pathogenic variants in the Cbl ubiquitin ligase gene, (CBL; HGNC:1541). Due to the proposed mechanism indicating the CBL gene's relationship to the RAS-MAPK pathway and the phenotypic presentation similar to that of the RASopathies, CBL-related disorder should be considered a RASopathy disorder. Though there is a wide spectrum of phenotypic variability, broadly, patients with CBL-related disorder have presented with developmental delay, intellectual disability, neurodevelopmental alterations, prenatal lymphatic anomalies, cardiac malformations as well as vascular anomalies particularly affecting the brain (e.g. Moya-moya arteriopathies), craniofacial features indicative of a RASopathy, hypotonia, feeding difficulties, edema of the legs, musculoskeletal and respiratory thorax abnormalities, ectodermal features including cafe-au-lait spots, immunological and hematological disorders and susceptibility to tumors diagnosed as juvenile myelomonocytic leukemia (JMML) that is usually self-remitting. Note tumor risk beyond JMML has not yet been thoroughly assessed. Due to the clinical presentation of a broad spectrum of these and other phenotypes in patients with variants in CBL, these conditions are currently defined by experts in reference to the causal gene, CBL (PMID's: 20619386, 25283271, 25358541, 28589114, 28414188, 28343148, 24458550, 29259247, 26911351, 21901340, 25952305). The mechanism for disease is unknown. In summary, CBL is definitively associated with autosomal dominant CBL-related disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen RASopathy Gene Curation Expert Panel on 1/7/2019 (SOP Version 5).
Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12 7
14
12
Bülow L et al. 2015 Feb (PMID:25358541); Seaby EG et al. 2017 May 22 (PMID:28589114); Coe RR et al. 2017 Jul (PMID:28414188); Guey S et al. 2017 Aug (PMID:28343148);
Proband with predicted or proven null variant 1.5 0-2 10
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 1
0.5
0.5
Hyakuna N et al. 2015 Mar (PMID:25283271);
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
1
Non-patient cells 0.5 0 - 1 2 1
Martinelli S et al. 2010 Aug 13 (PMID:20619386); Nadeau SA et al. 2017 Mar 3 (PMID:28082680);
Models Non-human model organism 2 0 - 4 4 2 2 2
Nakata Y et al. 2017 Apr 13 (PMID:28209720); Rathinam C et al. 2010 Oct 19 (PMID:20951944);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 3

 


 

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
(0-18)
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 3 15 YES
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Definitive
04/23/2020
EXPERT CURATION (DATE)
Definitive
04/29/2019
EVIDENCE SUMMARY
CBL was first reported in relation to autosomal dominant CBL-related disorders in 2010 (Martinelli et al., PMID 20619386). At least 9 variants (e.g. missense, splice site) have been reported in humans. Evidence supporting this gene-disease relationship includes case level data and experimental data including a functional alteration study expressing patient variants in heterologous cell lines and two different mouse models (PMIDs 20619386, 28082680, 28209720, 20951944). CBL-related disorder is a genetic condition caused by pathogenic variants in the Cbl ubiquitin ligase gene, (CBL; HGNC:1541). Due to the proposed mechanism indicating the CBL gene's relationship to the RAS-MAPK pathway and the phenotypic presentation similar to that of the RASopathies, CBL-related disorder should be considered a RASopathy disorder. Though there is a wide spectrum of phenotypic variability, broadly, patients with CBL-related disorder have presented with developmental delay, intellectual disability, neurodevelopmental alterations, prenatal lymphatic anomalies, cardiac malformations as well as vascular anomalies particularly affecting the brain (e.g. Moya-moya arteriopathies), craniofacial features indicative of a RASopathy, hypotonia, feeding difficulties, edema of the legs, musculoskeletal and respiratory thorax abnormalities, ectodermal features including cafe-au-lait spots, immunological and hematological disorders and susceptibility to tumors diagnosed as juvenile myelomonocytic leukemia (JMML) that is usually self-remitting. Note tumor risk beyond JMML has not yet been thoroughly assessed. Due to the clinical presentation of a broad spectrum of these and other phenotypes in patients with variants in CBL, these conditions are currently defined by experts in reference to the causal gene, CBL (PMID's: 20619386, 25283271, 25358541, 28589114, 28414188, 28343148, 24458550, 29259247, 26911351, 21901340, 25952305). The mechanism for disease is unknown. In summary, CBL is definitively associated with autosomal dominant CBL-related disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen RASopathy Gene Curation Expert Panel on 1/7/2019 (SOP Version 5).