ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

  • 11q23.3
  • GRCh37/hg19 chr11: 119,076,986-119,178,859
  • View: NCBI | Ensembl | UCSC
  • GRCh38/hg38 chr11: 119,206,339-119,308,149
  • View: NCBI | Ensembl | UCSC
Select assembly: (NC_000011.9) (NC_000011.10)

Haploinsufficiency phenotype comments:

Germline variants in CBL have been observed in individuals with a Noonan-like disorder, with and without Juvenile Myelomonocytic Leukemia (JMML). Bulow et al. 2015 (PMID:25358541) describe 2 patients with de novo missense variants and 1 with a de novo splice acceptor site variant. None of the variants suggest loss of function. No functional studies were performed. All three have similar prenatal features and Noonan like disorder. Martinelli et al. 2010 (PMID:20619386) describe patients missense variants. Functional studies on two of the variants suggests a dominant negative mechanism. Martinelli et al. 2015 (PMID:25952305) identified 5 patients with CBL variants (1 in frame deletion, 1 missense, 2 splice site, 1 transversion predicted to cause a premature termination p.Tyr235*). Functional studies of the two splice site variants show complete or partial deletions of exon 8. Western blot analysis of the CBL-Tyr235* showed reduced expression, however cells expressing the CBL-Tyr235* mutant showed enhanced constituative and EGF-induced ERK and AKT phosphorylation, suggesting a dominant negative effect. Additional report Hayakuna et al. 2015 (PMID 25283271) reported a missense mutation. At this time no variants or expression studies appear to support haploinsufficiency as the disease causing mechanism.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity