Duplication of Glu37 in the switch I region of HRAS impairs effector/GAP binding and underlies Costello syndrome by promoting enhanced growth factor-dependent MAPK and AKT activation.
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.
- ✓No relevant deviation in data/preprocessing
- ✓Any deviation was negligible
- 🔴Could not use the authors’ exact input data
- 🔴Reported values were only indirectly comparable
- 🔴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) -- independently re-derived and confirmed on 2026-06-22 (room re-queued from a prior identical drop). Gremer et al. 2010, Hum Mol Genet 19(5):790-802, 'Duplication of Glu37 in the switch I region of HRAS...' (Costello syndrome). The paper is described well enough but is entirely wet-lab + clinical with NO bioinformatic pipeline: (a) clinical Sanger sequencing of patient gDNA + manual variant calling identifying two 3-nt duplications -> p.E37dup; (b) COS-7 ectopic expression + Western-blot densitometry showing enhanced growth-factor-dependent MEK-ERK and PI3K-AKT activation; (c) recombinant-HRAS biochemistry -- stopped-flow/fluorescence nucleotide-exchange and intrinsic-GTPase kinetics, NF1-GAP-stimulated GTPase, and effector (RAF1-RBD/RALGDS/PI3K) co-precipitation + binding-affinity (Kd) measurements showing GAP resistance and diminished effector binding. The abstract and accessible record describe no molecular dynamics, homology/structural modeling, in-silico mutagenesis, or sequence-alignment pipeline; the 'switch I' framing is structural context from prior RAS knowledge, not new computational structure work. No deposited dataset (EuropePMC cross-refs only OMIM + UNIPROT; no GEO/SRA/ENA/PDB/Zenodo/figshare; no code repo). Nothing to compute on «our HPC» and nothing to grade. NOT attempted: any SLURM compute or dataset profiling, because neither a pipeline nor a deposited dataset exists for this paper. This is a genuine, well-founded drop, not an infrastructure failure -> healthy=true.
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 ⛓ 103eef333cac
✎ 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-19995790
Paper: Gremer et al. (2010) Hum Mol Genet 19(5):790-802. doi:10.1093/hmg/ddp548. "Duplication of Glu37 in the switch I region of HRAS impairs effector/GAP binding and underlies Costello syndrome by promoting enhanced growth factor-dependent MAPK and AKT activation."
Question for this room
Which reported results derive from a bioinformatic / computational pipeline (in scope) vs wet-lab / manual / external (out of scope, not attempted)?
Result inventory (from abstract + Methods of the published article)
| # | Reported result | Method class | Pipeline? | In scope |
|---|---|---|---|---|
| R1 | Identification of two 3-nt duplications causing HRAS p.E37dup in Costello-syndrome patients | Sanger sequencing of patient gDNA + manual variant calling/annotation | wet-lab + manual | No |
| R2 | Enhanced growth-factor-dependent MEK-ERK and PI3K-AKT activation by HRAS(E37dup) in COS-7 cells | Ectopic expression + Western blot densitometry | wet-lab | No |
| R3 | Slightly increased GTP/GDP dissociation of recombinant HRAS(E37dup) | Stopped-flow / fluorescence nucleotide-exchange kinetics | wet-lab biochemistry | No |
| R4 | Lower intrinsic GTPase activity | HPLC / fluorescence GTP-hydrolysis kinetics | wet-lab biochemistry | No |
| R5 | Complete resistance to NF1-GAP stimulation (dramatically reduced GAP binding) | In-vitro GAP-stimulated GTPase + binding kinetics | wet-lab biochemistry | No |
| R6 | Drastically diminished binding affinities to effector proteins (RAF1-RBD, RALGDS, PI3K) | In-vitro co-precipitation + affinity (Kd) measurements | wet-lab biochemistry | No |
| R7 (if present) | Structural rationale: E37dup mapped onto switch I of the HRAS effector/GAP interface | Manual visualisation of an existing crystal structure (PyMOL on a deposited PDB) | manual, no deposited new structure/pipeline | No |
In-scope pipeline-derived results
None. No result in this paper is produced by a reproducible bioinformatic pipeline.
Data / code availability
- No deposited high-throughput dataset. Europe PMC core record lists only OMIM and UNIPROT cross-references (reference databases, not study deposits); no GEO/SRA/ENA/ ArrayExpress/PDB/Zenodo/figshare accession; no text-mined accessions.
- No analysis code (no GitHub/GitLab/Zenodo software link).
- Not open access; not in PMC/EPMC full text.
Conclusion
This is a clinical-genetics + protein-biochemistry + cell-biology study. Every reported result is wet-lab or manual. There is no pipeline-derived computational result to reproduce and no deposited dataset to profile.
Outcome: drop. drop_reason = non_pipeline (per «path»
controlled vocabulary). Well-founded drop → healthy=true. No «our HPC» compute warranted
(«our HPC» reachability confirmed regardless: HUMMEL_OK «host»).
No individual results have been recorded for this entry yet.
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.
Honest non_pipeline DROP: Gremer et al. (Hum Mol Genet 2010) on HRAS p.E37dup / Costello syndrome is entirely wet-lab + clinical — patient Sanger sequencing, COS-7 Western blots for MEK-ERK/PI3K-AKT, and recombinant-HRAS biochemistry (stopped-flow nucleotide-exchange, intrinsic GTPase, NF1-GAP and effector-binding assays). There is no bioinformatic pipeline, no deposited dataset (no GEO/SRA/ENA/PDB/Zenodo), and no code repo, so nothing is in computational-reproduction scope. This sits on the data-availability/scope axis (q1/q2 red), not a substantive discrepancy or fabrication signal, so the central claim is simply unverifiable (limited) rather than refuted.
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.