{"gene":"TNNC1","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2015,"finding":"Cardiac troponin C (cTnC) is composed of two globular EF-hand domains connected by a flexible linker. The C-domain (cCTnC) contains two high-affinity Ca2+/Mg2+-binding sites that are constitutively occupied under physiologic conditions, stabilizing an open conformation anchored to the troponin complex. The regulatory N-domain (cNTnC) contains a single low-affinity Ca2+-binding site; Ca2+ binding favors an open conformation that engages the switch region of troponin I, releasing inhibitory regions of troponin I from actin to allow contraction.","method":"Review synthesizing structural and functional studies (NMR, crystallography, in vitro biochemical assays, mutagenesis)","journal":"Gene","confidence":"High","confidence_rationale":"Tier 1 / Strong — synthesis of multiple independent structural and biochemical studies (NMR, crystal structures, mutagenesis, reconstitution assays) replicated across many labs","pmids":["26232335"],"is_preprint":false},{"year":2008,"finding":"HCM-associated missense mutations in TNNC1 (A8V, C84Y, D145E) increase Ca2+ sensitivity of force development and force recovery in reconstituted skinned fiber assays, consistent with a gain-of-function mechanism at the myofilament level. E134D showed no change in these parameters.","method":"Recombinant mutant cTnC proteins reconstituted into skinned cardiac fibers; Ca2+-force relationship measurements; actomyosin ATPase assays","journal":"Journal of molecular and cellular cardiology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with functional readout replicated for multiple mutations across two independent studies (PMID:18572189, PMID:22815480)","pmids":["18572189"],"is_preprint":false},{"year":2011,"finding":"DCM-associated TNNC1 rare variants (Y5H, M103I) decrease Ca2+ sensitivity of force development in skinned fiber reconstitution assays, opposite to HCM mutations. M103I abolishes and Y5H diminishes the effects of PKA phosphorylation on Ca2+ sensitivity, and M103I decreases actomyosin ATPase activation at high Ca2+. CD spectroscopy showed that the mutants (except I148V in Ca2+/Mg2+ condition) reduced α-helical content, indicating structural perturbation.","method":"Recombinant mutant cTnC proteins reconstituted into porcine papillary skinned fibers; actomyosin ATPase assays; circular dichroism spectroscopy; PKA phosphorylation experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal in vitro methods (skinned fiber reconstitution, ATPase assay, CD spectroscopy, PKA phosphorylation) in a single rigorous study","pmids":["21832052"],"is_preprint":false},{"year":2012,"finding":"The TNNC1-A31S mutation increases Ca2+ affinity in isolated cTnC, in the troponin complex, in the thin filament, and (to a lesser degree) in the thin filament with myosin subfragment 1. Reconstituted skinned fibers showed increased Ca2+ sensitivity of force development without affecting maximal force, and 50% mutant:50% WT actomyosin ATPase assays showed intermediate Ca2+ sensitivity. Circular dichroism indicated no global secondary structure change.","method":"Skinned fiber reconstitution; actomyosin ATPase assay; fluorescence Ca2+ binding studies; circular dichroism spectroscopy","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal in vitro methods (skinned fiber reconstitution, ATPase assay, fluorescence binding, CD) in a single rigorous study","pmids":["22815480"],"is_preprint":false},{"year":2015,"finding":"Knock-in mice expressing the TNNC1-A8V mutation show dose-dependent increases in Ca2+ sensitivity of contraction in skinned fibers, reduced diastolic sarcomere length, increased shortening, prolonged Ca2+ and contractile transients in intact cardiomyocytes, and slower relaxation on flash photolysis of diazo-2. These changes lead to diastolic dysfunction and cardiac remodeling in vivo, establishing that the A8V mutation increases Ca2+-binding affinity of the thin filament.","method":"Knock-in mouse model; echocardiography; pressure-volume studies; skinned fiber Ca2+-force relationships; liquid chromatography-mass spectrometry for myofilament incorporation; intact cardiomyocyte Ca2+ transients; flash photolysis of diazo-2","journal":"Circulation. Cardiovascular genetics","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vivo knock-in model combined with multiple orthogonal cellular and biochemical readouts establishing mechanism","pmids":["26304555"],"is_preprint":false},{"year":2022,"finding":"HCM-associated TNNC1 variants (A8V, L29Q, A31S) elevate the binding affinity of cTnC for both Ca2+ and Mg2+ at the regulatory site II of the N-domain. Variants adjacent to the EF-hand motif of site II (L48Q, Q50R, C84Y) have a more significant effect on binding affinity and thermodynamics. Physiological concentrations of Mg2+ may compete with Ca2+ at site II, modulating Ca2+ sensitivity of contraction.","method":"Isothermal titration calorimetry (ITC) with recombinant mutant cTnC proteins; thermodynamic integration (TI) computational simulations","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — rigorous in vitro ITC combined with computational simulation, but single lab study","pmids":["35838319"],"is_preprint":false},{"year":2021,"finding":"The de novo TNNC1-G34S mutation impairs Ca2+-regulated force production in skinned cardiomyocytes and fibers. The mutant cTnC shows altered interaction with actin and disrupted inter-subunit interactions within the troponin complex, and compromises the structural integrity of reconstituted thin filaments. The protein quality control system is affected in patient myocardial tissue. Troponin-targeting agents levosimendan and EGCg partially stabilized thin filament structure and ameliorated contractile function in vitro.","method":"Skinned cardiomyocytes and fibers; reconstituted thin filament assays; protein interaction assays; patient myocardial tissue analysis; drug treatment experiments","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 1-2 / Weak — multiple in vitro functional methods but single study; patient tissue data limited","pmids":["34502534"],"is_preprint":false},{"year":2014,"finding":"In ovarian cancer cells, MFAP5 stromal signaling activates FAK, which in turn activates CREB, leading to upregulation of TNNC1; this FAK/CREB/TNNC1 axis mediates MFAP5-driven ovarian cancer cell motility and invasion. Knockdown of MFAP5 with siRNA nanoparticles decreased tumour growth and metastasis in vivo.","method":"siRNA knockdown; functional migration/invasion assays; in vivo mouse tumour model; pathway inhibition experiments","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with defined cellular phenotype and pathway placement, supported by in vivo data, single lab","pmids":["25277212"],"is_preprint":false},{"year":2021,"finding":"TNNC1 knockout in SKOV-3 ovarian cancer cells (via CRISPR/Cas9) reduces proliferation, colony formation, migration, and invasion. TNNC1 loss decreases phosphorylated AKT (Ser-473, Thr-308) and inactive GSK-3β, downregulates SNAIL and SLUG (relocating them to cytoplasm), decreases N-cadherin and vimentin while increasing E-cadherin, and suppresses F-actin polymerization, indicating that TNNC1 promotes EMT and actin dynamics in cancer cells.","method":"CRISPR/Cas9 knockout; western blot for EMT markers and AKT/GSK-3β phosphorylation; migration/invasion assays; F-actin staining","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean CRISPR KO with defined molecular pathway readouts and multiple orthogonal phenotypic assays, single lab","pmids":["33592378"],"is_preprint":false},{"year":2020,"finding":"In lung adenocarcinoma cells, ectopic TNNC1 expression inhibits KRASG12D-mediated anchorage-independent growth and colony formation, induces DNA damage, cell cycle arrest, and apoptosis. KRAS suppression enhances TNNC1 expression, suggesting TNNC1 acts downstream of KRAS as a tumor suppressor. RNAi-mediated TNNC1 knockdown enhances in vitro invasiveness.","method":"Ectopic TNNC1 overexpression; siRNA knockdown; colony formation assay; anchorage-independent growth assay; flow cytometry for apoptosis/cell cycle; DNA damage assay","journal":"Molecules and cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays (overexpression and KD) with specific cellular phenotype readouts, pathway placement via KRAS epistasis, single lab","pmids":["32638704"],"is_preprint":false},{"year":2020,"finding":"TNNC1 promotes gemcitabine resistance in non-small cell lung cancer by activating cytoprotective autophagy. FOXO3 negatively regulates this axis: silencing FOXO3 in GEM-resistant cells rescues autophagy weakened by TNNC1 knockdown. Blocking autophagy with 3-methyladenine restores chemotherapy sensitivity.","method":"siRNA knockdown; forced overexpression; flow cytometry; LC3 punctate assay; 3-methyladenine autophagy inhibition; FOXO3 loss-of-function epistasis","journal":"Medical science monitor","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional assays with pathway placement via epistasis but single lab, limited mechanistic depth for the TNNC1-specific mechanism","pmids":["32946432"],"is_preprint":false},{"year":2024,"finding":"KDM5D demethylase suppresses H3K4me3 at the E2F1 promoter, reducing E2F1 expression. E2F1 transcription factor binds the TNNC1 promoter and activates TNNC1 transcription (confirmed by ChIP and dual luciferase reporter assay). KDM5D overexpression thus reduces TNNC1 expression in HCC cells through the KDM5D/E2F1/TNNC1 axis, inhibiting cancer cell proliferation, migration, and invasion.","method":"ChIP assay for H3K4me3 and E2F1 promoter occupancy; dual luciferase reporter assay; western blot; overexpression/knockdown; in vivo nude mouse xenograft","journal":"Antioxidants & redox signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase reporter directly demonstrate E2F1 binding to TNNC1 promoter, complemented by in vivo data, single lab","pmids":["38504588"],"is_preprint":false},{"year":2020,"finding":"LukS-PV downregulates TNNC1 expression in HCC cells and inhibits HCC cell migration. LukS-PV inhibits phosphorylation of PI3K/AKT by targeting TNNC1, placing TNNC1 upstream of PI3K/AKT in regulating HCC cell migration.","method":"Scratch assay; western blot; RNA sequencing; quantitative proteomics; KEGG/GSEA pathway analysis; siRNA/overexpression","journal":"OncoTargets and therapy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — indirect placement via expression and pathway analysis with limited direct mechanistic validation of TNNC1-PI3K interaction, single lab","pmids":["33116603"],"is_preprint":false},{"year":1997,"finding":"The human TNNC1 gene was mapped to the short arm of chromosome 3, between markers D3S3118 and GCT4B10, by somatic cell hybrid and radiation hybrid panel analysis.","method":"Somatic cell hybrid PCR analysis; Genebridge4 radiation hybrid panel mapping","journal":"Annals of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Strong — direct chromosomal mapping by two independent hybrid panel methods, replicated","pmids":["9365790"],"is_preprint":false}],"current_model":"Cardiac troponin C (TNNC1) is the Ca2+-sensing subunit of the troponin complex on the thin filament: its C-domain binds Ca2+/Mg2+ constitutively to anchor the complex, while Ca2+ binding to the single regulatory site in the N-domain triggers an open conformation that engages the troponin I switch region, releasing inhibitory contacts with actin to activate contraction; HCM-associated mutations increase Ca2+ (and Mg2+) affinity at this regulatory site—thereby increasing myofilament Ca2+ sensitivity—while DCM-associated mutations decrease Ca2+ sensitivity and impair PKA-mediated modulation, and beyond striated muscle TNNC1 participates in cancer-relevant signaling (FAK/CREB axis, AKT/EMT, autophagy via FOXO3) and is transcriptionally regulated by the KDM5D/E2F1 axis."},"narrative":{"mechanistic_narrative":"TNNC1 encodes cardiac troponin C, the Ca2+-sensing subunit of the thin-filament troponin complex that couples cytosolic Ca2+ flux to sarcomeric contraction: its C-terminal globular domain holds two high-affinity Ca2+/Mg2+ sites that are constitutively occupied to anchor the complex, while its regulatory N-domain carries a single low-affinity Ca2+ site whose occupancy drives an open conformation that engages the troponin I switch region and relieves actin inhibition to permit contraction [PMID:26232335]. Disease-associated missense variants act through opposite effects on this Ca2+ switch: HCM mutations (A8V, A31S, L29Q, and others) raise the affinity of regulatory site II for both Ca2+ and Mg2+, increasing myofilament Ca2+ sensitivity of force development [PMID:18572189, PMID:22815480, PMID:35838319], whereas DCM-associated variants (Y5H, M103I) lower Ca2+ sensitivity and additionally blunt PKA-mediated modulation of the thin filament [PMID:21832052]. An A8V knock-in mouse reproduces this gain-of-function, producing prolonged Ca2+ and contractile transients, slowed relaxation, diastolic dysfunction, and cardiac remodeling in vivo [PMID:26304555]. Beyond striated muscle, TNNC1 functions in cancer-cell signaling: it is induced downstream of MFAP5–FAK–CREB signaling to promote ovarian cancer motility [PMID:25277212], drives AKT/GSK-3β-dependent EMT and F-actin dynamics [PMID:33592378], and is transcriptionally activated by E2F1 under control of the KDM5D demethylase [PMID:38504588], with both tumor-promoting and tumor-suppressive roles reported across tissue contexts [PMID:32638704].","teleology":[{"year":1997,"claim":"Establishing the chromosomal location of human TNNC1 provided the genomic anchor needed to link the gene to inherited disease loci.","evidence":"Somatic cell hybrid and radiation hybrid panel mapping placing TNNC1 on chromosome 3p","pmids":["9365790"],"confidence":"Medium","gaps":["Does not address protein function or regulation","No disease association established at this stage"]},{"year":2008,"claim":"The question of how HCM mutations alter contraction was answered by showing they confer a myofilament-level gain of function via increased Ca2+ sensitivity.","evidence":"Recombinant mutant cTnC reconstituted into skinned cardiac fibers with Ca2+-force and actomyosin ATPase readouts","pmids":["18572189"],"confidence":"High","gaps":["Mechanism of the affinity change at the atomic level not resolved","Whether all listed variants act identically unclear (E134D showed no effect)"]},{"year":2011,"claim":"DCM variants were shown to act in the opposite direction from HCM variants, decreasing Ca2+ sensitivity and impairing PKA modulation, establishing a bidirectional disease mechanism.","evidence":"Skinned fiber reconstitution, actomyosin ATPase, circular dichroism, and PKA phosphorylation assays with recombinant mutants","pmids":["21832052"],"confidence":"High","gaps":["Structural basis linking helical content loss to functional change not defined","In vivo cardiac consequences not tested"]},{"year":2012,"claim":"The A31S study traced increased Ca2+ sensitivity directly to elevated Ca2+ affinity at successive levels of thin-filament assembly, connecting the molecular defect to contractile output.","evidence":"Ca2+ binding by fluorescence, skinned fiber force, actomyosin ATPase, and CD across isolated cTnC, troponin, and thin filament","pmids":["22815480"],"confidence":"High","gaps":["No in vivo validation in this study","Maximal force unaffected, leaving downstream remodeling triggers unexplained"]},{"year":2015,"claim":"An A8V knock-in mouse established that increased thin-filament Ca2+ affinity is sufficient to cause diastolic dysfunction and cardiac remodeling in vivo, moving the mechanism from the test tube to the whole heart.","evidence":"Knock-in mouse with echocardiography, pressure-volume studies, intact cardiomyocyte Ca2+ transients, and diazo-2 flash photolysis","pmids":["26304555"],"confidence":"High","gaps":["Therapeutic reversal of the phenotype not tested","Generalizability to other HCM variants not addressed"]},{"year":2021,"claim":"The G34S variant extended the disease logic beyond simple Ca2+ affinity, showing that disrupted inter-subunit and actin interactions destabilize the thin filament and engage protein quality control, and that troponin-targeting drugs can partially correct it.","evidence":"Skinned cardiomyocyte/fiber assays, reconstituted thin filament and interaction assays, patient myocardial tissue, and levosimendan/EGCg treatment","pmids":["34502534"],"confidence":"Medium","gaps":["Single study with limited patient tissue","Drug effects in vitro only, no in vivo efficacy"]},{"year":2022,"claim":"Quantitative thermodynamics resolved that HCM variants raise affinity for both Ca2+ and Mg2+ at site II, introducing Mg2+ competition as a modulator of contractile Ca2+ sensitivity.","evidence":"Isothermal titration calorimetry and thermodynamic integration simulations on recombinant mutants","pmids":["35838319"],"confidence":"Medium","gaps":["Single-lab measurement","Physiological relevance of Mg2+ competition not tested in cells or in vivo"]},{"year":2024,"claim":"Beyond contraction, TNNC1 was placed in cancer signaling networks: it is induced via MFAP5/FAK/CREB and E2F1/KDM5D axes and feeds AKT-driven EMT and autophagy, with context-dependent oncogenic and tumor-suppressive roles.","evidence":"siRNA/CRISPR perturbation, EMT and AKT/GSK-3β marker blots, ChIP and luciferase reporter for E2F1 promoter binding, and xenograft models across ovarian, lung, and hepatocellular cancers","pmids":["25277212","33592378","32638704","38504588"],"confidence":"Medium","gaps":["Direction of effect differs between cancer types and is unreconciled","Direct molecular activity of TNNC1 in non-muscle cells not defined","How a sarcomeric Ca2+ sensor functions in cancer signaling is mechanistically unexplained"]},{"year":null,"claim":"The molecular basis for TNNC1's non-muscle, cancer-associated functions remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No biochemical activity or binding partner established for TNNC1 outside the troponin complex","Reconciliation of tumor-promoting versus tumor-suppressive roles lacking","Subcellular localization in cancer cells not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[0,3,5]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,6,8]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,6]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,8]}],"pathway":[{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[0,1,4]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,8]}],"complexes":["troponin complex","cardiac thin filament"],"partners":["TNNI3","ACTC1","MFAP5","E2F1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P19429","full_name":"Troponin I, cardiac muscle","aliases":["Cardiac troponin I"],"length_aa":210,"mass_kda":24.0,"function":"Troponin I is the inhibitory subunit of troponin, the thin filament regulatory complex which confers calcium-sensitivity to striated muscle actomyosin ATPase activity","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/P19429/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TNNC1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TNNC1","total_profiled":1310},"omim":[{"mim_id":"615396","title":"LEFT VENTRICULAR NONCOMPACTION 10; LVNC10","url":"https://www.omim.org/entry/615396"},{"mim_id":"613243","title":"CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 13; CMH13","url":"https://www.omim.org/entry/613243"},{"mim_id":"611879","title":"CARDIOMYOPATHY, DILATED, 1Z; CMD1Z","url":"https://www.omim.org/entry/611879"},{"mim_id":"600958","title":"MYOSIN-BINDING PROTEIN C, CARDIAC; MYBPC3","url":"https://www.omim.org/entry/600958"},{"mim_id":"192600","title":"CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 1; CMH1","url":"https://www.omim.org/entry/192600"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Actin filaments","reliability":"Approved"},{"location":"Mitochondria","reliability":"Approved"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"heart muscle","ntpm":8750.1},{"tissue":"skeletal muscle","ntpm":19761.9},{"tissue":"tongue","ntpm":11563.6}],"url":"https://www.proteinatlas.org/search/TNNC1"},"hgnc":{"alias_symbol":[],"prev_symbol":["TNNC"]},"alphafold":{"accession":"P19429","domains":[{"cath_id":"1.20.5","chopping":"43-80","consensus_level":"medium","plddt":96.6466,"start":43,"end":80},{"cath_id":"1.20.5","chopping":"90-140","consensus_level":"medium","plddt":92.8155,"start":90,"end":140},{"cath_id":"1.20.5","chopping":"150-182","consensus_level":"medium","plddt":68.31,"start":150,"end":182}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P19429","model_url":"https://alphafold.ebi.ac.uk/files/AF-P19429-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P19429-F1-predicted_aligned_error_v6.png","plddt_mean":78.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TNNC1","jax_strain_url":"https://www.jax.org/strain/search?query=TNNC1"},"sequence":{"accession":"P19429","fasta_url":"https://rest.uniprot.org/uniprotkb/P19429.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P19429/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P19429"}},"corpus_meta":[{"pmid":"20215591","id":"PMC_20215591","title":"Coding sequence rare variants identified in MYBPC3, MYH6, TPM1, TNNC1, and TNNI3 from 312 patients with familial or idiopathic dilated cardiomyopathy.","date":"2010","source":"Circulation. Cardiovascular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20215591","citation_count":199,"is_preprint":false},{"pmid":"25277212","id":"PMC_25277212","title":"Calcium-dependent FAK/CREB/TNNC1 signalling mediates the effect of stromal MFAP5 on ovarian cancer metastatic potential.","date":"2014","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/25277212","citation_count":113,"is_preprint":false},{"pmid":"18572189","id":"PMC_18572189","title":"Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C.","date":"2008","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/18572189","citation_count":106,"is_preprint":false},{"pmid":"26232335","id":"PMC_26232335","title":"Structure and function of cardiac troponin C (TNNC1): Implications for heart failure, cardiomyopathies, and troponin modulating drugs.","date":"2015","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/26232335","citation_count":99,"is_preprint":false},{"pmid":"22815480","id":"PMC_22815480","title":"A mutation in TNNC1-encoded cardiac troponin C, TNNC1-A31S, predisposes to hypertrophic cardiomyopathy and ventricular fibrillation.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22815480","citation_count":51,"is_preprint":false},{"pmid":"21832052","id":"PMC_21832052","title":"Functional characterization of TNNC1 rare variants identified in dilated cardiomyopathy.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21832052","citation_count":49,"is_preprint":false},{"pmid":"26304555","id":"PMC_26304555","title":"In Vivo Analysis of Troponin C Knock-In (A8V) Mice: Evidence that TNNC1 Is a Hypertrophic Cardiomyopathy Susceptibility Gene.","date":"2015","source":"Circulation. Cardiovascular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26304555","citation_count":38,"is_preprint":false},{"pmid":"27604170","id":"PMC_27604170","title":"Evidence for troponin C (TNNC1) as a gene for autosomal recessive restrictive cardiomyopathy with fatal outcome in infancy.","date":"2016","source":"American journal of medical genetics. 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Part A","url":"https://pubmed.ncbi.nlm.nih.gov/39248034","citation_count":1,"is_preprint":false},{"pmid":"28056232","id":"PMC_28056232","title":"[Analysis of cardiac troponin C gene TNNC1 c. G175C mutation in a Chinese pedigree with familial hypertrophic cardiomyopathy and the correlation between genotype and phenotype].","date":"2016","source":"Zhonghua xin xue guan bing za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/28056232","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.06.25.661563","title":"Spatial isoform sequencing at sub-micrometer single-cell resolution reveals novel patterns of spatial isoform variability in brain cell types","date":"2025-06-25","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.25.661563","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.29.24311195","title":"ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel: Reappraisal of Genes associated with Hypertrophic Cardiomyopathy","date":"2024-08-01","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.29.24311195","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14928,"output_tokens":3977,"usd":0.05222,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11807,"output_tokens":3048,"usd":0.067617,"stage2_stop_reason":"end_turn"},"total_usd":0.119837,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"Cardiac troponin C (cTnC) is composed of two globular EF-hand domains connected by a flexible linker. The C-domain (cCTnC) contains two high-affinity Ca2+/Mg2+-binding sites that are constitutively occupied under physiologic conditions, stabilizing an open conformation anchored to the troponin complex. The regulatory N-domain (cNTnC) contains a single low-affinity Ca2+-binding site; Ca2+ binding favors an open conformation that engages the switch region of troponin I, releasing inhibitory regions of troponin I from actin to allow contraction.\",\n      \"method\": \"Review synthesizing structural and functional studies (NMR, crystallography, in vitro biochemical assays, mutagenesis)\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — synthesis of multiple independent structural and biochemical studies (NMR, crystal structures, mutagenesis, reconstitution assays) replicated across many labs\",\n      \"pmids\": [\"26232335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"HCM-associated missense mutations in TNNC1 (A8V, C84Y, D145E) increase Ca2+ sensitivity of force development and force recovery in reconstituted skinned fiber assays, consistent with a gain-of-function mechanism at the myofilament level. E134D showed no change in these parameters.\",\n      \"method\": \"Recombinant mutant cTnC proteins reconstituted into skinned cardiac fibers; Ca2+-force relationship measurements; actomyosin ATPase assays\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with functional readout replicated for multiple mutations across two independent studies (PMID:18572189, PMID:22815480)\",\n      \"pmids\": [\"18572189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"DCM-associated TNNC1 rare variants (Y5H, M103I) decrease Ca2+ sensitivity of force development in skinned fiber reconstitution assays, opposite to HCM mutations. M103I abolishes and Y5H diminishes the effects of PKA phosphorylation on Ca2+ sensitivity, and M103I decreases actomyosin ATPase activation at high Ca2+. CD spectroscopy showed that the mutants (except I148V in Ca2+/Mg2+ condition) reduced α-helical content, indicating structural perturbation.\",\n      \"method\": \"Recombinant mutant cTnC proteins reconstituted into porcine papillary skinned fibers; actomyosin ATPase assays; circular dichroism spectroscopy; PKA phosphorylation experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal in vitro methods (skinned fiber reconstitution, ATPase assay, CD spectroscopy, PKA phosphorylation) in a single rigorous study\",\n      \"pmids\": [\"21832052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The TNNC1-A31S mutation increases Ca2+ affinity in isolated cTnC, in the troponin complex, in the thin filament, and (to a lesser degree) in the thin filament with myosin subfragment 1. Reconstituted skinned fibers showed increased Ca2+ sensitivity of force development without affecting maximal force, and 50% mutant:50% WT actomyosin ATPase assays showed intermediate Ca2+ sensitivity. Circular dichroism indicated no global secondary structure change.\",\n      \"method\": \"Skinned fiber reconstitution; actomyosin ATPase assay; fluorescence Ca2+ binding studies; circular dichroism spectroscopy\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal in vitro methods (skinned fiber reconstitution, ATPase assay, fluorescence binding, CD) in a single rigorous study\",\n      \"pmids\": [\"22815480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Knock-in mice expressing the TNNC1-A8V mutation show dose-dependent increases in Ca2+ sensitivity of contraction in skinned fibers, reduced diastolic sarcomere length, increased shortening, prolonged Ca2+ and contractile transients in intact cardiomyocytes, and slower relaxation on flash photolysis of diazo-2. These changes lead to diastolic dysfunction and cardiac remodeling in vivo, establishing that the A8V mutation increases Ca2+-binding affinity of the thin filament.\",\n      \"method\": \"Knock-in mouse model; echocardiography; pressure-volume studies; skinned fiber Ca2+-force relationships; liquid chromatography-mass spectrometry for myofilament incorporation; intact cardiomyocyte Ca2+ transients; flash photolysis of diazo-2\",\n      \"journal\": \"Circulation. Cardiovascular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vivo knock-in model combined with multiple orthogonal cellular and biochemical readouts establishing mechanism\",\n      \"pmids\": [\"26304555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HCM-associated TNNC1 variants (A8V, L29Q, A31S) elevate the binding affinity of cTnC for both Ca2+ and Mg2+ at the regulatory site II of the N-domain. Variants adjacent to the EF-hand motif of site II (L48Q, Q50R, C84Y) have a more significant effect on binding affinity and thermodynamics. Physiological concentrations of Mg2+ may compete with Ca2+ at site II, modulating Ca2+ sensitivity of contraction.\",\n      \"method\": \"Isothermal titration calorimetry (ITC) with recombinant mutant cTnC proteins; thermodynamic integration (TI) computational simulations\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — rigorous in vitro ITC combined with computational simulation, but single lab study\",\n      \"pmids\": [\"35838319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The de novo TNNC1-G34S mutation impairs Ca2+-regulated force production in skinned cardiomyocytes and fibers. The mutant cTnC shows altered interaction with actin and disrupted inter-subunit interactions within the troponin complex, and compromises the structural integrity of reconstituted thin filaments. The protein quality control system is affected in patient myocardial tissue. Troponin-targeting agents levosimendan and EGCg partially stabilized thin filament structure and ameliorated contractile function in vitro.\",\n      \"method\": \"Skinned cardiomyocytes and fibers; reconstituted thin filament assays; protein interaction assays; patient myocardial tissue analysis; drug treatment experiments\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Weak — multiple in vitro functional methods but single study; patient tissue data limited\",\n      \"pmids\": [\"34502534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In ovarian cancer cells, MFAP5 stromal signaling activates FAK, which in turn activates CREB, leading to upregulation of TNNC1; this FAK/CREB/TNNC1 axis mediates MFAP5-driven ovarian cancer cell motility and invasion. Knockdown of MFAP5 with siRNA nanoparticles decreased tumour growth and metastasis in vivo.\",\n      \"method\": \"siRNA knockdown; functional migration/invasion assays; in vivo mouse tumour model; pathway inhibition experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with defined cellular phenotype and pathway placement, supported by in vivo data, single lab\",\n      \"pmids\": [\"25277212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TNNC1 knockout in SKOV-3 ovarian cancer cells (via CRISPR/Cas9) reduces proliferation, colony formation, migration, and invasion. TNNC1 loss decreases phosphorylated AKT (Ser-473, Thr-308) and inactive GSK-3β, downregulates SNAIL and SLUG (relocating them to cytoplasm), decreases N-cadherin and vimentin while increasing E-cadherin, and suppresses F-actin polymerization, indicating that TNNC1 promotes EMT and actin dynamics in cancer cells.\",\n      \"method\": \"CRISPR/Cas9 knockout; western blot for EMT markers and AKT/GSK-3β phosphorylation; migration/invasion assays; F-actin staining\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean CRISPR KO with defined molecular pathway readouts and multiple orthogonal phenotypic assays, single lab\",\n      \"pmids\": [\"33592378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In lung adenocarcinoma cells, ectopic TNNC1 expression inhibits KRASG12D-mediated anchorage-independent growth and colony formation, induces DNA damage, cell cycle arrest, and apoptosis. KRAS suppression enhances TNNC1 expression, suggesting TNNC1 acts downstream of KRAS as a tumor suppressor. RNAi-mediated TNNC1 knockdown enhances in vitro invasiveness.\",\n      \"method\": \"Ectopic TNNC1 overexpression; siRNA knockdown; colony formation assay; anchorage-independent growth assay; flow cytometry for apoptosis/cell cycle; DNA damage assay\",\n      \"journal\": \"Molecules and cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays (overexpression and KD) with specific cellular phenotype readouts, pathway placement via KRAS epistasis, single lab\",\n      \"pmids\": [\"32638704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TNNC1 promotes gemcitabine resistance in non-small cell lung cancer by activating cytoprotective autophagy. FOXO3 negatively regulates this axis: silencing FOXO3 in GEM-resistant cells rescues autophagy weakened by TNNC1 knockdown. Blocking autophagy with 3-methyladenine restores chemotherapy sensitivity.\",\n      \"method\": \"siRNA knockdown; forced overexpression; flow cytometry; LC3 punctate assay; 3-methyladenine autophagy inhibition; FOXO3 loss-of-function epistasis\",\n      \"journal\": \"Medical science monitor\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional assays with pathway placement via epistasis but single lab, limited mechanistic depth for the TNNC1-specific mechanism\",\n      \"pmids\": [\"32946432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KDM5D demethylase suppresses H3K4me3 at the E2F1 promoter, reducing E2F1 expression. E2F1 transcription factor binds the TNNC1 promoter and activates TNNC1 transcription (confirmed by ChIP and dual luciferase reporter assay). KDM5D overexpression thus reduces TNNC1 expression in HCC cells through the KDM5D/E2F1/TNNC1 axis, inhibiting cancer cell proliferation, migration, and invasion.\",\n      \"method\": \"ChIP assay for H3K4me3 and E2F1 promoter occupancy; dual luciferase reporter assay; western blot; overexpression/knockdown; in vivo nude mouse xenograft\",\n      \"journal\": \"Antioxidants & redox signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase reporter directly demonstrate E2F1 binding to TNNC1 promoter, complemented by in vivo data, single lab\",\n      \"pmids\": [\"38504588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LukS-PV downregulates TNNC1 expression in HCC cells and inhibits HCC cell migration. LukS-PV inhibits phosphorylation of PI3K/AKT by targeting TNNC1, placing TNNC1 upstream of PI3K/AKT in regulating HCC cell migration.\",\n      \"method\": \"Scratch assay; western blot; RNA sequencing; quantitative proteomics; KEGG/GSEA pathway analysis; siRNA/overexpression\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — indirect placement via expression and pathway analysis with limited direct mechanistic validation of TNNC1-PI3K interaction, single lab\",\n      \"pmids\": [\"33116603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The human TNNC1 gene was mapped to the short arm of chromosome 3, between markers D3S3118 and GCT4B10, by somatic cell hybrid and radiation hybrid panel analysis.\",\n      \"method\": \"Somatic cell hybrid PCR analysis; Genebridge4 radiation hybrid panel mapping\",\n      \"journal\": \"Annals of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct chromosomal mapping by two independent hybrid panel methods, replicated\",\n      \"pmids\": [\"9365790\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Cardiac troponin C (TNNC1) is the Ca2+-sensing subunit of the troponin complex on the thin filament: its C-domain binds Ca2+/Mg2+ constitutively to anchor the complex, while Ca2+ binding to the single regulatory site in the N-domain triggers an open conformation that engages the troponin I switch region, releasing inhibitory contacts with actin to activate contraction; HCM-associated mutations increase Ca2+ (and Mg2+) affinity at this regulatory site—thereby increasing myofilament Ca2+ sensitivity—while DCM-associated mutations decrease Ca2+ sensitivity and impair PKA-mediated modulation, and beyond striated muscle TNNC1 participates in cancer-relevant signaling (FAK/CREB axis, AKT/EMT, autophagy via FOXO3) and is transcriptionally regulated by the KDM5D/E2F1 axis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TNNC1 encodes cardiac troponin C, the Ca2+-sensing subunit of the thin-filament troponin complex that couples cytosolic Ca2+ flux to sarcomeric contraction: its C-terminal globular domain holds two high-affinity Ca2+/Mg2+ sites that are constitutively occupied to anchor the complex, while its regulatory N-domain carries a single low-affinity Ca2+ site whose occupancy drives an open conformation that engages the troponin I switch region and relieves actin inhibition to permit contraction [#0]. Disease-associated missense variants act through opposite effects on this Ca2+ switch: HCM mutations (A8V, A31S, L29Q, and others) raise the affinity of regulatory site II for both Ca2+ and Mg2+, increasing myofilament Ca2+ sensitivity of force development [#1, #3, #5], whereas DCM-associated variants (Y5H, M103I) lower Ca2+ sensitivity and additionally blunt PKA-mediated modulation of the thin filament [#2]. An A8V knock-in mouse reproduces this gain-of-function, producing prolonged Ca2+ and contractile transients, slowed relaxation, diastolic dysfunction, and cardiac remodeling in vivo [#4]. Beyond striated muscle, TNNC1 functions in cancer-cell signaling: it is induced downstream of MFAP5–FAK–CREB signaling to promote ovarian cancer motility [#7], drives AKT/GSK-3\\u03b2-dependent EMT and F-actin dynamics [#8], and is transcriptionally activated by E2F1 under control of the KDM5D demethylase [#11], with both tumor-promoting and tumor-suppressive roles reported across tissue contexts [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Establishing the chromosomal location of human TNNC1 provided the genomic anchor needed to link the gene to inherited disease loci.\",\n      \"evidence\": \"Somatic cell hybrid and radiation hybrid panel mapping placing TNNC1 on chromosome 3p\",\n      \"pmids\": [\"9365790\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not address protein function or regulation\", \"No disease association established at this stage\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"The question of how HCM mutations alter contraction was answered by showing they confer a myofilament-level gain of function via increased Ca2+ sensitivity.\",\n      \"evidence\": \"Recombinant mutant cTnC reconstituted into skinned cardiac fibers with Ca2+-force and actomyosin ATPase readouts\",\n      \"pmids\": [\"18572189\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of the affinity change at the atomic level not resolved\", \"Whether all listed variants act identically unclear (E134D showed no effect)\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"DCM variants were shown to act in the opposite direction from HCM variants, decreasing Ca2+ sensitivity and impairing PKA modulation, establishing a bidirectional disease mechanism.\",\n      \"evidence\": \"Skinned fiber reconstitution, actomyosin ATPase, circular dichroism, and PKA phosphorylation assays with recombinant mutants\",\n      \"pmids\": [\"21832052\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis linking helical content loss to functional change not defined\", \"In vivo cardiac consequences not tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"The A31S study traced increased Ca2+ sensitivity directly to elevated Ca2+ affinity at successive levels of thin-filament assembly, connecting the molecular defect to contractile output.\",\n      \"evidence\": \"Ca2+ binding by fluorescence, skinned fiber force, actomyosin ATPase, and CD across isolated cTnC, troponin, and thin filament\",\n      \"pmids\": [\"22815480\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No in vivo validation in this study\", \"Maximal force unaffected, leaving downstream remodeling triggers unexplained\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"An A8V knock-in mouse established that increased thin-filament Ca2+ affinity is sufficient to cause diastolic dysfunction and cardiac remodeling in vivo, moving the mechanism from the test tube to the whole heart.\",\n      \"evidence\": \"Knock-in mouse with echocardiography, pressure-volume studies, intact cardiomyocyte Ca2+ transients, and diazo-2 flash photolysis\",\n      \"pmids\": [\"26304555\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Therapeutic reversal of the phenotype not tested\", \"Generalizability to other HCM variants not addressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The G34S variant extended the disease logic beyond simple Ca2+ affinity, showing that disrupted inter-subunit and actin interactions destabilize the thin filament and engage protein quality control, and that troponin-targeting drugs can partially correct it.\",\n      \"evidence\": \"Skinned cardiomyocyte/fiber assays, reconstituted thin filament and interaction assays, patient myocardial tissue, and levosimendan/EGCg treatment\",\n      \"pmids\": [\"34502534\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single study with limited patient tissue\", \"Drug effects in vitro only, no in vivo efficacy\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Quantitative thermodynamics resolved that HCM variants raise affinity for both Ca2+ and Mg2+ at site II, introducing Mg2+ competition as a modulator of contractile Ca2+ sensitivity.\",\n      \"evidence\": \"Isothermal titration calorimetry and thermodynamic integration simulations on recombinant mutants\",\n      \"pmids\": [\"35838319\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab measurement\", \"Physiological relevance of Mg2+ competition not tested in cells or in vivo\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Beyond contraction, TNNC1 was placed in cancer signaling networks: it is induced via MFAP5/FAK/CREB and E2F1/KDM5D axes and feeds AKT-driven EMT and autophagy, with context-dependent oncogenic and tumor-suppressive roles.\",\n      \"evidence\": \"siRNA/CRISPR perturbation, EMT and AKT/GSK-3\\u03b2 marker blots, ChIP and luciferase reporter for E2F1 promoter binding, and xenograft models across ovarian, lung, and hepatocellular cancers\",\n      \"pmids\": [\"25277212\", \"33592378\", \"32638704\", \"38504588\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direction of effect differs between cancer types and is unreconciled\", \"Direct molecular activity of TNNC1 in non-muscle cells not defined\", \"How a sarcomeric Ca2+ sensor functions in cancer signaling is mechanistically unexplained\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular basis for TNNC1's non-muscle, cancer-associated functions remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No biochemical activity or binding partner established for TNNC1 outside the troponin complex\", \"Reconciliation of tumor-promoting versus tumor-suppressive roles lacking\", \"Subcellular localization in cancer cells not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [0, 3, 5]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 6, 8]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 8]}\n    ],\n    \"complexes\": [\"troponin complex\", \"cardiac thin filament\"],\n    \"partners\": [\"TNNI3\", \"ACTC1\", \"MFAP5\", \"E2F1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}