Cerebral vascular malformations

Gene: CBL

Green List (high evidence)

The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.

Created: 10 Dec 2025, 2:36 p.m. | Last Modified: 10 Dec 2025, 2:36 p.m.

Panel Version: 4.9

Comment on list classification: As reviewed by Alexandra Njegic, there are five patients from three unrelated families reported with three different CBL variants and cerebral arteriopathy in PMID:32637631, and one patient was reported with the previously identified de novo splice variant in CBL gene in PMID:37778001. The patient from PMID:37778001 also had a maternally inherited VUS variant in RNF213 gene. This is also some functional evidence available.

There is sufficient evidence available for the promotion of this gene to green rating in the next GMS update. However, it has been tagged for expert review from the GMS.

Created: 22 Apr 2025, 7:24 p.m. | Last Modified: 22 Apr 2025, 7:24 p.m.

Panel Version: 3.29

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
cerebral arterial disease, MONDO:0006693; Moyamoya disease, MONDO:0016820

Publications

• 32637631
• 37778001

Green List (high evidence)

32637631: 5 individuals from 3 separate families. Authors identified 3 variants (1 transmitted [parent reported as affected], 2 de novo); 1 delins c.1110_1112delATA; 1 intronic splice variant c.1228-2A>G (seen in PMID 28343148) and 1 missense c.1100C>A. In vitro studies (delins and splice variant) using patient-derived PBMCs showed impaired Cbl-mediated degradation of cell surface receptors; patient-derived dermal fibroblasts transformed to SMCs showed increased proliferation, migration and MAPK expression. At the time of publication, no patients had a reported haematological malignancy.
37778001: 1 patient with a maternally inherited RNF213 VUS also harboured a pathogenic CBL heterozygous de novo variant (same splice variant identified in PMID 32637631 and 28343148). No report of a haematological malignancy.

Created: 8 Apr 2025, 5 p.m. | Last Modified: 8 Apr 2025, 5 p.m.

Panel Version: 3.26

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Cerebral arteriopathy; Moyamoya Disease

Publications

• 32637631
• 37778001

After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains amber. The reviewers disagree with inclusion of this gene as there are only 2x variants reported to be associated with CVM on HGMD. A very strong possibility of incidental findings if variants only previously reported in association with JMML.

Created: 30 Jan 2023, 4:01 p.m. | Last Modified: 30 Jan 2023, 4:01 p.m.

Panel Version: 2.68

Green List (high evidence)

This gene is associated with a phenotype in OMIM and Gene2Phenotype. Based on expert reviews and literature, there is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.

Created: 3 Aug 2021, 9:17 a.m. | Last Modified: 3 Aug 2021, 9:17 a.m.

Panel Version: 2.57

Green List (high evidence)

PMID: 28343148 two unrelated cases with de novo CBL variants in context of early onset severe bilateral moyamoya and subtle features of RASopathy but no haematological malignancy. One had het splice variant c.1228-2A>G previously demonstrated to lead to a partial or complete exon 9 deletion; another had het missense NM_005188.3:c.1111T>A; p.Tyr371Asn within the linker domain, PMID: 25283271 - single case with Noonan like features, JMML, moyamoya and neovascular glaucoma. PMID: 28589114 - single case presenting with atypical hemolytic uremic syndrome, moyamoya, and mild Noonan-like phenotype. Denovo heterozygous splicing variant in CBL (c.1096-1G>T)

Created: 6 Jul 2021, 9:48 a.m. | Last Modified: 6 Jul 2021, 9:48 a.m.

Panel Version: 2.55

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
early-onset moyamoya angiopathy; Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia, 613563

Publications

• 28343148
• 25283271
• 28589114

I don't know

New gene - deemed relevant to the GMS panel R336 Cerebral vascular malformations

Created: 29 Nov 2019, 3:41 p.m. | Last Modified: 29 Nov 2019, 5:51 p.m.

Panel Version: 1.67

Comment on list classification: Changed rating from Red to Amber - this gene was deemed relevant to the GMS panel R336 Cerebral vascular malformations.
This was gene was recommended to be rated as Green but after further clinical expert it was decided to rate as Amber until there was sufficient evidence.

Created: 29 Nov 2019, 3:36 p.m. | Last Modified: 29 Nov 2019, 5:51 p.m.

Panel Version: 1.67

Review from clinical expert (Vijeya Ganesan: GOSH / ICH): important association re leukaemia, green rating.

Created: 29 Nov 2019, 3:35 p.m. | Last Modified: 29 Nov 2019, 3:35 p.m.

Panel Version: 1.53

Green List (high evidence)

The addition of the CBL gene is supported by two publication as well as personal observations of the submitter
Sources: Literature, Research

Created: 14 Apr 2019, 4:42 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
early-onset moyamoya angiopathy

Publications

• 28343148
• 25283271

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments