RASopathy-associated CBL germline mutations cause aberrant ubiquitylation and trafficking of EGFR.
Part of the results reproduced; minor but material deviations remained.
Every item that counted toward this verdict, and the exact part of the reproduction that produced it.
- ✓Any deviation was negligible
- 🔴Could not use the authors’ exact input data
- 🔴Reported values were only indirectly comparable
- 🟡A deviation arose in the data or preprocessing
- 🟡A deviation was attributed to the published material
- 🟡Reported values were not (fully) derivable from the shared data
- 🟡The central claim did not (fully) hold under reproduction
- 🟡Overall, the reproduction showed a material discrepancy
▸Reproduction agent’s raw note
DROP / non_pipeline (re-verified). Brand K, Kentsch H, Glashoff C, Rosenberger G. 'RASopathy-associated CBL germline mutations cause aberrant ubiquitylation and trafficking of EGFR.' Hum Mutat 2014;35(11):1372-81; DOI 10.1002/humu.22682. This is a pure wet-lab functional cell-biology study: three RASopathy/Noonan-like CBL germline missense variants (p.K382E, p.D390Y, p.R420Q) were expressed in COS-7 cells and characterized by flow cytometry + immunofluorescence microscopy (surface vs intracellular EGFR), fluorescent-EGF uptake assays, co-immunoprecipitation + anti-ubiquitin Western blots, EGF-chase degradation blots (manual densitometry), and anti-phospho-ERK Western blots. ALL five reported results are qualitative/relative wet-lab measurements of the authors' own instrument images; none is pipeline-derived. There is NO bioinformatic/computational analysis (no sequence-conservation alignment, no structure/PDB mapping, no variant-effect prediction reported), NO deposited public data (no GEO/SRA/ENA/ArrayExpress/PRIDE/figshare/zenodo/dbGaP/EGA accession; Europe PMC hasData=Y resolves only to GOA + UniProt + GlyGen cross-references that merely reference the paper, not primary deposits; isOpenAccess=N, hasSuppl=N), and NO code repository (enrichment + Europe PMC text-mining: no code link). Nothing is computationally reproducible and nothing could be run on «our HPC». What we did NOT attempt: any of R1-R5, because they are wet-lab and out of scope by design. This is a clean, well-founded non_pipeline drop; verdict is PROVISIONAL and must be independently checked by a human.
These records describe the outcome of reproduction attempts carried out autonomously by brainbox using large language models (LLMs). They are not peer review, not an audit, and not a determination of error or misconduct by any author. A verdict reflects what one attempt could or could not reproduce — which may depend on data access, undocumented parameters, the computing environment, or the depth of effort — and not a judgement of the people who did the work. We can be wrong, and we correct mistakes quickly: every record carries a “report an error” button.
Assessment versions
Every reproduction run is kept as an immutable version — anchored to the data as it stood, with a tamper-evident chain hash. A rerun (e.g. after an author updates a deposit) adds a new version; the previous one stays on record.
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v1 current initial assessmentassessed: 2026-06-19 ⛓ f776b9c38d08
✎ I am an author of this paper
Updated or fixed a deposit, or is there an erratum? Ask us to re-run the metrics. We verify by email first; the new result is published as a new version with full history — nothing is overwritten.
Provenance — full disclosure
When this reproduction was carried out, which methodology version was used, and by whom — so the record can be audited and checked independently.
- Reproduced
- 2026-06-22
- Rubric version
- v1.0
- Assessed by
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🤖 AI curator · claude (ai-curator room) · v1.0 · run #1 2026-06-19no human curator yet
- Last updated
- 2026-08-05
Provisional, curator- or AI-assessed, and independently checkable. A reproduction outcome states what one attempt could reproduce — not a judgement of the authors.
What was reproduced
The exact results taken into scope, with each reported value next to the value our attempt produced.
Scope analysis — pmid-25178484
- Title: RASopathy-associated CBL germline mutations cause aberrant ubiquitylation and trafficking of EGFR.
- Authors: Brand K, Kentsch H, Glashoff C, Rosenberger G.
- Venue: Human Mutation. 2014 Nov;35(11):1372-81.
- DOI: 10.1002/humu.22682 · PMID: 25178484 · PMCID: none (not in PMC; not open access)
Summary of the study
A functional cell-biology characterization of three RASopathy/Noonan-syndrome-like CBL germline missense variants (p.K382E, p.D390Y, p.R420Q). The variants were expressed in COS-7 (and the paper's other mammalian) cells, and their effect on ligand-induced EGFR trafficking, ubiquitylation, degradation and downstream ERK phosphorylation was measured.
Reported results and their experimental origin
| # | Reported result | Method (as described) | In scope? |
|---|---|---|---|
| R1 | Mutant CBL → increased surface EGFR, reduced intracellular EGFR | Flow cytometry / immunofluorescence microscopy (wet-lab) | NO |
| R2 | Decreased receptor-mediated EGF uptake | Fluorescent-EGF uptake assay + microscopy/flow (wet-lab) | NO |
| R3 | Impaired CBL-mediated EGFR ubiquitylation | Co-IP + anti-ubiquitin Western blot (wet-lab) | NO |
| R4 | Impaired EGFR degradation | EGF-chase + anti-EGFR Western blot, densitometry (wet-lab) | NO |
| R5 | Enhanced ERK phosphorylation in mutant-CBL cells | anti-pERK Western blot, densitometry (wet-lab) | NO |
Scope verdict: OUT OF SCOPE — non_pipeline
There is no bioinformatic pipeline in this paper. Every reported result is a wet-lab measurement (flow cytometry, confocal/fluorescence microscopy, EGF-uptake assay, co-immunoprecipitation, Western blotting). Quantification, where present, is manual densitometry / mean-fluorescence-intensity readout of the authors' own microscope/cytometer/blot images — there is no public raw image/cytometry data deposit and no analysis code from which any value could be regenerated.
Reproducibility-surface checks (control-plane, zero compute)
- Code: none. No GitHub/GitLab/Zenodo/Bitbucket repository referenced anywhere
(enrichment + Europe PMC text-mining: no code link). →
no_code - Data: no GEO / SRA / ENA / ArrayExpress / PRIDE / figshare / zenodo / dbGaP /
EGA accession. Europe PMC
hasData:Yresolves only to a Gene Ontology Annotation (GOA) cross-reference (curators reading the paper to extract GO terms) — NOT a primary-data deposit. →no_data_accession - Expected result: results are qualitative/relative ("increased", "reduced", "impaired") with figure-based densitometry; no public substrate to recompute.
The paper is described well enough scientifically, but it is the wrong kind of paper for a computational-pipeline reproduction: there is nothing to run on «our HPC» because there is no deposited data and no pipeline. This is a clean, well-founded non_pipeline drop, not an our-side failure.
Assessments & scoring basis
Each contributor’s verdict, the per-question basis, and the auditable, itemised worksheet behind it.
An automated assessment. It can flag an open question for review but can never, on its own, record a discrepancy verdict (C5) against a paper.
Every item that counted toward this verdict, and the exact part of the reproduction that produced it.
Clean non_pipeline drop. Brand et al. (Hum Mutat 2014;35(11):1372-81; DOI 10.1002/humu.22682) is a pure wet-lab functional study of three RASopathy CBL germline variants (p.K382E/p.D390Y/p.R420Q) characterized by flow cytometry, IF microscopy, EGF-uptake, co-IP/anti-ubiquitin and anti-pERK Western blots — there is no pipeline, no deposited data (Europe PMC hasData is only a GOA cross-reference), and no code. None of R1-R5 is computationally reproducible, so the blocker is data/scope availability on the input side, not an authors' defect and not our methodology. Accordingly q5/q7/q8 are held at yellow (non-assessable, not fabrication-suspect) to keep this a fair drop rather than a critical flag.
Automated reproduction checks whether a published result can be regenerated from the paper’s described methods and shared data. When something does not reproduce, that is not a claim of error or misconduct — most often it reflects under-described methods, software or environment differences, or gaps in data access, and some of the pre-print papers in the queue may carry issues their authors had no part in. The goal is shared awareness that rigorous, fully-described methods help everyone — never a judgement of any author.
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Reproduction footprint
claude-opus-4-8Measured resources invested to assess this paper — sanitised (machine class only, no job ids/paths). Compute = HPC accounting (SLURM); tokens = the AI agent's session.