# NM_005188.4(CBL):c.1099_1101del (p.Gln367del)

https://sugi.bio/variant/cbl-p-gln367del

## Summary

**CBL p.Gln367del (c.1099_1101del)** is classified **Pathogenic/Likely pathogenic** in CBL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-22). No gnomAD frequency available for this variant; Associated with CBL-related disorder.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs1555230070 · 3 submitters · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the CBL gene that is considered likely disease-causing, submitted by 3 submitters, and is linked to CBL-related disorder.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017577/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CBL](https://sugi.bio/atlas/gene/CBL/) |
| Protein change (HGVS p.) | p.Gln367del |
| Coding change (HGVS c.) | c.1099_1101del |
| MANE Select transcript | [NM_005188](https://www.ncbi.nlm.nih.gov/nuccore/NM_005188) |
| dbSNP | [rs1555230070](https://www.ncbi.nlm.nih.gov/snp/rs1555230070/) |
| Variant type | Deletion |
| Location | chr11:119278167-119278169 (GRCh38) |
| ClinVar | [VCV523667](https://www.ncbi.nlm.nih.gov/clinvar/variation/523667/) |

**All HGVS expressions:** `LRG_608:g.76890_76892del`, `NC_000011.10:g.119278169_119278171del`, `NC_000011.9:g.119148879_119148881del`, `NG_016808.1:g.76890_76892del`, `NM_005188.2:c.1099_1101del`, `NM_005188.3:c.1099_1101delCAA`, `NM_005188.4:c.1099_1101del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 11.894, GERP 2.08, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **in-frame indel**.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**CBL** population constraint: LOEUF 0.622, pLI 0.00033116, missense-Z 1.6974; ClinGen dosage — haploinsufficiency 0, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **CBL-related disorder** — Definitive (AD)

## Protein context {#protein}

Residue **367** lies in the 'required for ubiquitination of spred2' region; an α-helix; a UniProt-annotated variant site (in nsll); the 'linker' region.

AlphaFold model confidence (whole protein): pLDDT 64.27, 36% of residues very-high.

**34 experimental structure(s)** (PDB): [1B47](https://www.rcsb.org/structure/1B47), [1FBV](https://www.rcsb.org/structure/1FBV), [1YVH](https://www.rcsb.org/structure/1YVH), [2CBL](https://www.rcsb.org/structure/2CBL), [2JUJ](https://www.rcsb.org/structure/2JUJ), [2K4D](https://www.rcsb.org/structure/2K4D) — incl. mutant structure 5HKX.

## What this gene does {#gene-function}

*Describes the biological roles of CBL (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** CBL's established molecular role includes SH3 domain binding. p.Gln367del falls in the required for ubiquitination of spred2 region. In Reactome, CBL is annotated in disease pathway(s) including **Constitutive Signaling by EGFRvIII**, **Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants**.

**Disease mechanism (Reactome):** CBL loss or alteration is curated in [Constitutive Signaling by EGFRvIII](https://reactome.org/content/detail/R-HSA-5637810), [Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants](https://reactome.org/content/detail/R-HSA-1236382), [FLT3 signaling by CBL mutants](https://reactome.org/content/detail/R-HSA-9706377).

### Pathways affected {#pathways}

CBL participates in **20 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Constitutive Signaling by EGFRvIII](https://reactome.org/content/detail/R-HSA-5637810) | curated |
| ⚕ [Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants](https://reactome.org/content/detail/R-HSA-1236382) | curated |
| ⚕ [FLT3 signaling by CBL mutants](https://reactome.org/content/detail/R-HSA-9706377) | curated |
| ⚕ [InlB-mediated entry of Listeria monocytogenes into host cell](https://reactome.org/content/detail/R-HSA-8875360) | electronic |
| [Cargo recognition for clathrin-mediated endocytosis](https://reactome.org/content/detail/R-HSA-8856825) | curated |
| [Clathrin-mediated endocytosis](https://reactome.org/content/detail/R-HSA-8856828) | curated |
| [EGFR downregulation](https://reactome.org/content/detail/R-HSA-182971) | curated |
| [Interleukin-6 signaling](https://reactome.org/content/detail/R-HSA-1059683) | curated |
| [Negative regulation of FGFR1 signaling](https://reactome.org/content/detail/R-HSA-5654726) | curated |
| [Negative regulation of FGFR2 signaling](https://reactome.org/content/detail/R-HSA-5654727) | curated |
| [Negative regulation of FGFR3 signaling](https://reactome.org/content/detail/R-HSA-5654732) | curated |
| [Negative regulation of FGFR4 signaling](https://reactome.org/content/detail/R-HSA-5654733) | curated |
| [Negative regulation of FLT3](https://reactome.org/content/detail/R-HSA-9706369) | curated |
| [Negative regulation of MET activity](https://reactome.org/content/detail/R-HSA-6807004) | curated |
| [PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1](https://reactome.org/content/detail/R-HSA-8849469) | curated |
| [Regulation of KIT signaling](https://reactome.org/content/detail/R-HSA-1433559) | curated |
| [Spry regulation of FGF signaling](https://reactome.org/content/detail/R-HSA-1295596) | curated |
| [TGF-beta receptor signaling activates SMADs](https://reactome.org/content/detail/R-HSA-2173789) | curated |
| [Regulation of signaling by CBL](https://reactome.org/content/detail/R-HSA-912631) | electronic |
| [Signaling by CSF1 (M-CSF) in myeloid cells](https://reactome.org/content/detail/R-HSA-9680350) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** SH3 domain binding, cadherin binding, ephrin receptor binding, ubiquitin protein ligase activity.

**Biological process:** ubiquitin-dependent protein catabolic process, protein ubiquitination, negative regulation of epidermal growth factor receptor signaling pathway, negative regulation of apoptotic process, positive regulation of receptor-mediated endocytosis, protein stabilization.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-05-22.

**Submitter consensus:** conflicting (2 Likely pathogenic, 1 Pathogenic).

**Submission history:** 3 submissions (2023–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Institute of Human Genetics, University of Goettingen | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-05-22 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2023-09-22 |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-09-22 |

## Associated conditions {#conditions}

[CBL-related disorder](https://sugi.bio/atlas/disease/cbl-related-disorder/).

**Reported phenotype names (ClinVar):** CBL-related disorder, not provided, none provided, NOONAN SYNDROME-LIKE DISORDER WITHOUT JUVENILE MYELOMONOCYTIC LEUKEMIA, CBL MUTATION-ASSOCIATED SYNDROME, CBL SYNDROME.

## Same-residue context {#hotspot}

Residue **367** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [CBL p.Gln367Arg](/variant/cbl-p-gln367arg), [CBL p.Gln367Pro](/variant/cbl-p-gln367pro). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CBL variant pages (same residue, condition, or type): [CBL p.Gln367Pro](/variant/cbl-p-gln367pro), [CBL c.1096-4_1096-1del](/variant/cbl-c-1096-minus-4-1096-minus-1del), [CBL p.Gln367Arg](/variant/cbl-p-gln367arg), [CBL c.2435-1_2435del](/variant/cbl-c-2435-minus-1-2435del), [CBL p.Ile664fs](/variant/cbl-p-ile664fs), [CBL p.Pro569del](/variant/cbl-p-pro569del), [CBL p.Thr364del](/variant/cbl-p-thr364del), [CBL c.1227+2_1227+6del](/variant/cbl-c-1227-plus-2-1227-plus-6del).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 523667). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*