Patient-initiated · computationally characterized · experimentally unresolved
44 curated public statements for the USH2A G1526R case. Each entry keeps its evidence category, sources, method, stated limitation and review status attached, so a reader can see exactly how far a statement goes.
Publication rule from the scientific handoff: only curated claims may inform public pages. Unsupported example statements recorded in the registry are internal review material and are never rendered as findings. 28 statements carry a locked scientific meaning: changing one requires a new source review, not a copy edit.
Category is shown as text and a border style, never as colour alone.
Reproducible identity, coordinate or sequence observation; not a physiological measurement.
USH2A-C001Sequence factLocked scientific meaning
NM_206933.4:c.4576G>A corresponds to NP_996816.3:p.Gly1526Arg and GRCh38 NC_000001.11:g.216175303C>T; USH2A is on the minus strand.
Limitation: Reference mapping does not identify a molecular mechanism.
USH2A-C002Sequence fact
At the normally spliced coding sequence, GGG becomes AGG, replacing glycine with arginine at residue 1526; the site lies in exon 21 of the classical references.
Limitation: This is the correctly spliced sequence consequence; actual RNA processing remains unmeasured.
USH2A-C004Sequence fact
The classical long reference encodes 5,202 amino acids (NP_996816.3), and the classical short reference encodes 1,546 amino acids (NP_009054.6).
Limitation: Reference sequence length does not measure isoform abundance or functional importance.
USH2A-C005Sequence fact
The two classical reference proteins share residues 1–1543; the short form then terminates with the distinct KCV sequence.
Limitation: Shared sequence does not establish equal effects in the two isoforms.
A named reference database annotation, with its source and scope; not automatically experimental proof.
USH2A-C003Reference annotation
USH2A encodes usherin and is associated in reference databases with Usher syndrome type 2A and nonsyndromic retinitis pigmentosa.
Limitation: Gene-level associations do not predict an individual outcome or establish this variant’s mechanism.
USH2A-C006Reference annotationLocked scientific meaning
The classical short transcript terminates in exon 21; the long transcript continues to exon 22 and downstream exons. The long-form 50-nt reconstruction cannot be transferred to the short transcript.
Limitation: Other annotated transcripts exist; physiological isoform contributions are unresolved.
USH2A-C007Reference annotation
The long-form annotation places the extracellular region at residues 32–5042, the transmembrane segment at 5043–5063 and the cytoplasmic region at 5064–5202; the classical short form lacks those long-form terminal regions.
Limitation: Topology is reference annotation, not a localization measurement in G1526R.
USH2A-C008Reference annotation
G1526 maps within UniProt laminin G-like domain 1 (LG1; 1517–1709), before the narrower Pfam core (1548–1678).
Limitation: A domain annotation does not establish a ligand-binding site or a required native conformation.
An output or descriptive comparison from a specified model under recorded assumptions.
USH2A-C010Computational predictionLocked scientific meaning
Archived SpliceAI, Pangolin and AlphaGenome analyses agree on enhancement at the cryptic donor-associated position and reduction at the annotated donor-associated position.
Limitation: Only AlphaGenome supplies the donor–acceptor pair here; Pangolin’s executed classification head does not separately label donor versus acceptor. Agreement is not independent experimental replication.
USH2A-C011Computational predictionLocked scientific meaning
AlphaGenome directly returned the minus-strand intron [216097213,216175301), connecting cryptic donor 216175302 to exon-22 acceptor 216097213 in retained-exonic-base coordinates.
Limitation: The interval is 0-based half-open; endpoint base coordinates are 1-based. A predicted pair is not an observed mature RNA.
USH2A-C012Computational predictionLocked scientific meaning
The 1,048,576-bp AlphaGenome context contains the relevant donor and acceptor; the 131,072-bp context excludes the exon-22 acceptor. The selected tissue tracks are embryonic camera-type eye and adult brain.
Limitation: The short context cannot assess the proposed pair; neither selected track is a retina/photoreceptor assay.
USH2A-C013Computational predictionLocked scientific meaning
Among 98 returned partners of the cryptic donor in the 1-Mb context, the exon-22 acceptor ranks first by ALT output in both selected tracks; the annotated junction still has higher ALT output than this cryptic junction.
Limitation: Ranking is within the returned candidate set and is not a transcript percentage, measured abundance or probability of an entire RNA.
USH2A-C014Computational predictionLocked scientific meaning
For the proposed junction, eye REF/ALT outputs are 0.0006493872497230768/0.005134492181241512 and brain REF/ALT outputs are 0.00025533069856464863/0.0007750487420707941.
Limitation: Unmodified model output scale; these values must not be rescaled into measured RNA fractions.
USH2A-C015Computational predictionLocked scientific meaning
Other returned pairings include intronic acceptors 216111456 and 216111459, exon-23 acceptor 216089139, internal exon-22 acceptor 216097159, and a weak short-terminal-exon candidate at 216175102; whole-exon21 skipping shows only a small pair-output increase.
Limitation: Intronic pairings lack complete onward exon definitions; the candidate list does not establish which RNAs exist.
USH2A-C021Computational prediction
The structural comparison reuses six matched WT/G1526R model pairs of residues 1364–1709, encompassing FNIII-4, the linker and complete LG1.
Limitation: These are twelve unrelaxed local predictions, not experimental structures or full-length native proteins.
USH2A-C022Computational predictionLocked scientific meaning
Matched local Cα RMSDs span 0.152–0.341 Å after LG1-core alignment, partly overlapping the 0.132–0.230 Å range among WT models.
Limitation: Descriptive model variability is not independent biological replication; small displacements do not demonstrate normal function.
USH2A-C023Computational predictionLocked scientific meaning
Target pLDDT ranges are 88.69–90.56 for WT and 78.00–83.56 for G1526R; pLDDT is model confidence, not an energy or native-function score.
Limitation: Lower confidence cannot be converted into a stability loss or functional percentage.
USH2A-C024Computational predictionLocked scientific meaning
Twenty-six of thirty primary Rosetta mutant structures failed the broad local covalent-geometry screen, so their large positive scores were excluded as quantitative evidence of native destabilization.
Limitation: This is a calculation-quality finding; it neither proves nor rules out biological destabilization.
USH2A-C025Computational predictionLocked scientific meaning
Spatial-neighbor flexibility reduced the Rosetta result to +13.706 and +9.135 REU in two tested inputs while removing gross geometry flags; positive reverse controls and protocol dependence still prevent a calibrated native folding-energy estimate.
Limitation: REU must not be converted into or averaged with kcal/mol; two sensitivity inputs do not validate the method.
USH2A-C026Computational predictionLocked scientific meaning
ThermoMPNN forward means were +1.288 and +1.306 predicted kcal/mol for LG1 and the larger context, while reverse means were approximately +0.060 and +0.058.
Limitation: These are learned-scale predictions, not measured native free energies; forward/reverse disagreement limits interpretation.
USH2A-C027Computational predictionLocked scientific meaning
Exploratory MD completed three paired WT/G1526R simulations of 20 ns each, plus a separately preserved 5-ns preparation sensitivity, for 125 ns total.
Limitation: The model is capped, isolated, aglycosylated LG1, with specified protonation and disulfide assumptions; it does not represent the entire protein.
USH2A-C028Computational predictionLocked scientific meaning
Across the three MD pairs, local RMSD differences in the common 10–20 ns window range from −0.664 to +1.185 Å and reverse direction; no uniform local dynamic defect or equilibrium convergence was established.
Limitation: Short folded-basin simulations do not measure folding free energy, unfolding kinetics or native cellular function.
A sequence/architecture consequence that follows only if the specified RNA or protein is produced.
USH2A-C016Conditional consequenceLocked scientific meaning
Using the predicted cryptic-to-exon22 junction while retaining all other long-reference junctions deletes exactly c.4578_4627: 50 nt, transcript bases 5017–5066 and genomic bases 216175252–216175301 inclusive.
Limitation: This full RNA is reconstructed, not emitted by AlphaGenome or detected experimentally.
USH2A-C017Conditional consequenceLocked scientific meaning
If the reconstructed transcript carrying the 50-nt deletion is translated from the reference start, codons 1526–1528 encode Arg–His–stop, giving a 1,527-amino-acid candidate product.
Limitation: The stop is codon 1528, not amino-acid length 1528; production of this protein has not been shown.
USH2A-C018Conditional consequenceLocked scientific meaning
In the reconstructed long transcript, the premature stop ends 124 nt before the next exon junction, a positional configuration compatible with potential nonsense-mediated mRNA decay (NMD).
Limitation: NMD has not been experimentally demonstrated, and neither its extent nor RNA depletion is known.
USH2A-C031Conditional consequenceLocked scientific meaning
A translated product of the deletion-containing transcript would lack the long protein’s downstream membrane and cytoplasmic regions; normally spliced G1526R retains their sequence.
Limitation: Neither retained sequence nor predicted truncation demonstrates actual protein abundance, localization or binding.
A finding directly tested in a cited published experiment, limited to that experiment and construct; not a G1526R result unless explicitly stated.
USH2A-C009Published experiment
Published biochemical experiments support interactions of USH2A cytoplasmic constructs with WHRN and PDZD7 in ankle-link complex studies.
Limitation: These are general construct-specific experiments, not G1526R tests or proof of a binding interface at residue 1526.
A biological quantity or mechanism that the available study does not establish.
USH2A-C019Unresolved questionLocked scientific meaning
The predicted deletion-containing splice product has not been experimentally observed in this project; actual abnormal RNA abundance is unknown.
Limitation: No RNA assay was performed in this computational study; this is an evidence gap, not a negative experimental result.
USH2A-C020Unresolved questionLocked scientific meaning
Isoform-specific functional contributions remain unresolved.
Limitation: Reference architecture does not establish tissue expression, compensation or relative physiological importance.
USH2A-C029Unresolved questionLocked scientific meaning
AlphaFold, Rosetta and MD do not establish native protein function in this study.
Limitation: Folding, maturation, delivery, interactions and turnover require appropriate experimental measurements.
USH2A-C030Unresolved questionLocked scientific meaning
The reviewed evidence does not establish a G1526-specific binding interface or a direct partner-binding defect.
Limitation: General complex membership and distant cytoplasmic interactions cannot be assigned to this extracellular residue.
USH2A-C032Unresolved questionLocked scientific meaning
The dominant pathogenic mechanism is unknown. RNA and protein effects could coexist, and the present evidence does not quantify their contributions.
Limitation: The RNA route is a testable priority, not an established predominant cause.
USH2A-C033Unresolved questionLocked scientific meaning
No therapeutic efficacy has been established by this project. A proposed splicing-restoration approach is a research hypothesis, not an available treatment.
Limitation: The study contains no intervention efficacy or safety experiment and supports no individual treatment recommendation.
A proposed comparison or assay; no result, scheduled work or resource commitment is implied.
USH2A-C036Proposed work
The first proposed RNA comparison is sequence-confirmed detection of native and alternative junctions in matched WT and variant contexts.
Limitation: A negative result requires adequate expression and assay sensitivity; minigenes do not reproduce the whole locus or retinal context.
USH2A-C037Proposed work
Quantifying native and alternative transcripts with NMD-aware controls would test RNA proportions and whether a sequence-confirmed abnormal product is preferentially depleted.
Limitation: Targeted PCR is not automatically quantitative; NMD perturbations can have broad effects and need matched controls.
USH2A-C038Proposed work
Transcriptomics with junction-to-transcript-end linkage could test which RNA products belong to long, short or other annotated isoforms.
Limitation: Sparse long reads do not establish absence or unbiased abundance; orthogonal quantitative measurements remain useful.
USH2A-C039Proposed work
Matched intron-free WT/G1526R protein expression, with RNA normalization, could test an amino-acid effect independently of altered splicing.
Limitation: Overexpression, construct boundaries and tags can obscure native behavior; an insensitive assay cannot exclude an effect.
USH2A-C040Proposed work
Protein biochemistry could compare defined LG1 or larger constructs for maturation, folding-related behavior and structural differences.
Limitation: Isolated-domain behavior may not transfer to native glycosylated usherin; a thermal shift is not automatically an equilibrium folding free energy.
USH2A-C041Proposed work
Human-cell, iPSC and retinal-organoid collaborations could test RNA processing and isoform-specific localization in relevant expression contexts.
Limitation: No cell line, organoid, human material, approval or committed facility is assumed; context relevance and maturation must be demonstrated.
USH2A-C043Proposed work
Isoform-specific localization, turnover and targeted interaction studies could follow a reproducible protein phenotype or a supported partner interface.
Limitation: Steady-state protein abundance confounds synthesis and degradation; arbitrary docking is not a substitute for mapped binding evidence.
A project-governance or study-scope statement, not a biological result.
USH2A-C034Project scope
This patient-initiated investigation uses public reference information and computational evidence to formulate testable molecular questions about USH2A G1526R.
Limitation: No patient identity, clinical history, family dataset or individual prognosis is presented.
USH2A-C035Project scopeLocked scientific meaning
This case concerns only USH2A c.4576G>A / p.Gly1526Arg and includes no private familial datasets, unpublished member records or association authorization to publish such records.
Limitation: Public scientific content is not permission to disclose personal or member data.
USH2A-C042Project scopeLocked scientific meaning
Laboratory capabilities are being sought; no laboratory or collaborator is represented as having committed resources.
Limitation: No invented affiliation, endorsement, collaborator, contact address or scheduled experiment may be added.
USH2A-C044Project scopeLocked scientific meaning
This handoff curates existing results and preserves the original research artifacts; it adds no new molecular predictions or wet-laboratory results.
Limitation: Content auditing is not independent peer review or experimental validation.