{"gene":"AMT","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":1994,"finding":"The human AMT gene (aminomethyltransferase, T-protein of the glycine cleavage system) was isolated, shown to consist of nine exons spanning ~6 kb, mapped to chromosomal subband 3p21.2-p21.1 by fluorescence in situ hybridization, and its 5'-flanking region characterized as lacking a TATAA sequence but containing putative glucocorticoid- and thyroid hormone-responsive elements with a single defined transcription initiation site.","method":"Genomic library screening, restriction mapping, PCR, DNA sequencing, primer extension, fluorescence in situ hybridization (FISH)","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1-2 — direct structural/genomic characterization of the human AMT gene with multiple orthogonal methods in a single study","pmids":["8188235"],"is_preprint":false},{"year":2006,"finding":"Comprehensive mutation analysis of 69 NKH families established that AMT (T-protein) mutations cause nonketotic hyperglycinemia; missense mutations were the most common disease-causing mutation type in AMT, and biallelic pathogenic AMT mutations were identified in a subset of NKH families. AMT mutations were found in 11 of 69 families, distinct from GLDC mutations.","method":"Complete coding-region sequencing of AMT, GLDC, and GCSH in NKH patient cohort; mutation characterization","journal":"Human mutation","confidence":"High","confidence_rationale":"Tier 2 — large cohort sequencing with systematic mutation identification, replicated across multiple families and labs","pmids":["16450403"],"is_preprint":false},{"year":2001,"finding":"Recurring mutations in the AMT (T-protein) gene were identified in NKH patients: R320H (7% of alleles) and a splice site mutation IVS7-1G>A (3% of alleles), with a novel point mutation N145I also described, establishing AMT as encoding the glycine cleavage T-protein whose loss of function causes NKH.","method":"DNA sequencing, PCR/restriction enzyme assays, allele frequency screening in NKH patient bank","journal":"Molecular genetics and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 — systematic mutation screening across patient cohort, single lab","pmids":["11286506"],"is_preprint":false},{"year":2001,"finding":"The first splice site mutation in the AMT gene (IVS7-1G→A) was identified in three unrelated NKH families, confirming AMT encodes the glycine cleavage T-protein and that splice-site loss of function mutations in AMT cause NKH.","method":"PCR/restriction enzyme mutation screening of 100 NKH alleles; Sanger sequencing","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 — mutation identified across multiple unrelated families, functionally consistent with NKH phenotype","pmids":["11139253"],"is_preprint":false},{"year":2002,"finding":"The murine Amt gene was cloned and sequenced, shown to consist of nine closely spaced exons within ~5 kb of genomic DNA encoding a 403-amino acid protein highly homologous to human aminomethyltransferase, with the Nicolin 1 gene (Nicn1) immediately upstream.","method":"Genomic cloning, sequencing, exon-intron mapping","journal":"DNA sequence","confidence":"Medium","confidence_rationale":"Tier 2 — direct structural characterization of the orthologous murine gene","pmids":["12487019"],"is_preprint":false},{"year":2000,"finding":"The canine AMT gene was mapped to chromosome 20q15.1→q15.2, shown to span 5 kb with nine exons, encoding a 403-amino acid protein with 88% identity to human aminomethyltransferase, closely linked to the TCTA gene.","method":"Genomic sequence analysis, gene mapping, sequence alignment","journal":"Cytogenetics and cell genetics","confidence":"Medium","confidence_rationale":"Tier 2 — direct genomic structural characterization of canine ortholog","pmids":["10894947"],"is_preprint":false},{"year":2003,"finding":"In NKH patients with unusual biochemical findings (residual glycine cleavage activity in liver or lymphoblasts, or abnormal amniotic fluid glycine/serine ratio with normal glycine), T-protein (AMT) defects accounted for >50% of cases, with novel AMT mutations identified (including R296H), establishing that AMT mutations can produce residual enzyme activity and atypical NKH presentations.","method":"Enzyme activity assays in liver and lymphoblasts, sequencing, PCR/restriction enzyme methods","journal":"Molecular genetics and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 — functional enzyme assays combined with mutation identification in patient cohort","pmids":["12948742"],"is_preprint":false},{"year":2016,"finding":"Analysis of 578 NKH families identified 410 unique mutations; AMT mutations (primarily missense, often recurring) were identified with biallelic pathogenic variants in 98% of AMT-affected subjects. Genotype in AMT correlated with attenuated vs. classic NKH phenotype in 15% of subjects.","method":"Sequencing, CNV analysis, genotype-phenotype correlation across large international cohort","journal":"Genetics in medicine","confidence":"High","confidence_rationale":"Tier 2 — large multi-center cohort with systematic mutation identification and genotype-phenotype correlation","pmids":["27362913"],"is_preprint":false},{"year":2022,"finding":"Novel compound heterozygous frameshift mutations in AMT exon 8 (c.977delA and c.982_983insG) were identified by whole-exome sequencing in a Chinese NKH patient, inherited from each parent, confirming autosomal recessive inheritance of AMT-related NKH.","method":"Whole-exome sequencing, Sanger sequencing validation, family segregation analysis","journal":"Frontiers in genetics","confidence":"Medium","confidence_rationale":"Tier 2 — WES with Sanger validation and family segregation, single case","pmids":["35646099"],"is_preprint":false}],"current_model":"Human AMT encodes aminomethyltransferase (T-protein), a component of the mitochondrial glycine cleavage system (EC 2.1.2.10) whose loss-of-function mutations—missense, frameshift, or splice-site, inherited in an autosomal recessive manner—cause nonketotic hyperglycinemia (NKH) by impairing glycine catabolism; the gene spans ~6 kb with nine exons at chromosomal locus 3p21.2-p21.1, and residual AMT enzyme activity correlates with attenuated clinical phenotypes."},"narrative":{"teleology":[{"year":1994,"claim":"Establishing the genomic structure and chromosomal location of human AMT resolved the gene architecture encoding the glycine cleavage T-protein, enabling subsequent mutation screening in NKH patients.","evidence":"Genomic library screening, restriction mapping, sequencing, primer extension, and FISH mapping to 3p21.2-p21.1","pmids":["8188235"],"confidence":"High","gaps":["No disease-causing mutations identified at this stage","Promoter elements described computationally but not functionally validated","No crystal structure of the human protein"]},{"year":2000,"claim":"Characterization of canine and murine AMT orthologs demonstrated high sequence conservation (88% identity to human) and identical nine-exon gene architecture, supporting functional conservation of aminomethyltransferase across mammals.","evidence":"Genomic cloning, sequencing, and gene mapping of canine (chr 20q15.1–q15.2) and murine Amt genes","pmids":["10894947","12487019"],"confidence":"Medium","gaps":["No functional assays performed in animal models to test enzymatic equivalence","No animal model of AMT deficiency generated"]},{"year":2001,"claim":"Identification of recurring AMT mutations (R320H, IVS7-1G>A) in unrelated NKH families established that loss of T-protein function directly causes nonketotic hyperglycinemia, distinguishing AMT-related NKH from GLDC-related NKH.","evidence":"Sanger sequencing and PCR/restriction enzyme screening across NKH patient cohorts from multiple unrelated families","pmids":["11286506","11139253"],"confidence":"Medium","gaps":["Functional impact of individual mutations not demonstrated by in vitro enzyme assays","Relative contribution of AMT vs. GLDC mutations to NKH prevalence not yet quantified in large cohorts"]},{"year":2003,"claim":"Demonstrating that AMT mutations can produce residual glycine cleavage activity and atypical NKH presentations revealed that AMT genotype modulates disease severity, not just presence or absence of disease.","evidence":"Enzyme activity assays in liver and lymphoblasts combined with mutation identification in patients with unusual biochemical profiles","pmids":["12948742"],"confidence":"Medium","gaps":["Structural basis for why specific mutations retain partial activity unknown","No recombinant expression system used to quantify individual mutant enzyme kinetics"]},{"year":2006,"claim":"Systematic sequencing of all three glycine cleavage genes across 69 NKH families quantified AMT mutations as the cause in ~16% of families, with missense mutations predominating, delineating the genetic landscape of AMT-related NKH.","evidence":"Complete coding-region sequencing of AMT, GLDC, and GCSH in a 69-family NKH cohort","pmids":["16450403"],"confidence":"High","gaps":["Deep intronic and regulatory variants not assessed","No functional validation of newly identified missense variants"]},{"year":2016,"claim":"Large-scale international genotype-phenotype analysis across 578 NKH families confirmed that AMT genotype predicts attenuated vs. classic NKH in a subset of patients, solidifying the correlation between residual T-protein function and clinical outcome.","evidence":"Sequencing and CNV analysis with phenotype correlation in a multi-center cohort of 578 families","pmids":["27362913"],"confidence":"High","gaps":["Mechanism by which specific AMT genotypes produce residual activity not structurally resolved","No therapeutic strategies targeting residual AMT activity tested"]},{"year":2022,"claim":"Discovery of novel compound heterozygous frameshift mutations in a Chinese NKH patient expanded the AMT mutational spectrum and confirmed autosomal recessive inheritance in a previously underrepresented population.","evidence":"Whole-exome sequencing with Sanger validation and family segregation analysis","pmids":["35646099"],"confidence":"Medium","gaps":["Single case report; population frequency of these alleles unknown","No functional assay of the truncated proteins"]},{"year":null,"claim":"The structural basis for differential residual activity of AMT missense variants, the precise mechanism of AMT's interaction with H-protein within the glycine cleavage complex, and whether pharmacological chaperones or gene therapy can rescue partial AMT deficiency remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of human AMT in complex with H-protein","No reconstituted in vitro system measuring kinetics of individual disease-causing mutants","No animal model of AMT-deficient NKH established for therapeutic testing"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1,6,7]}],"complexes":["glycine cleavage system"],"partners":["GLDC","GCSH"],"other_free_text":[]},"mechanistic_narrative":"AMT encodes aminomethyltransferase (T-protein), a mitochondrial enzyme of the glycine cleavage system that catalyzes the transfer of the aminomethyl moiety from the H-protein lipoyl arm to tetrahydrofolate, yielding 5,10-methylene-tetrahydrofolate and ammonia as part of glycine catabolism [PMID:8188235]. The human AMT gene spans approximately 6 kb with nine exons at chromosome 3p21.2-p21.1 and encodes a protein highly conserved across mammals [PMID:8188235, PMID:10894947]. Biallelic loss-of-function mutations in AMT—predominantly missense but also frameshift and splice-site variants—cause nonketotic hyperglycinemia (NKH), with residual AMT enzyme activity correlating with attenuated rather than classic disease presentation [PMID:16450403, PMID:27362913, PMID:12948742]."},"prefetch_data":{"uniprot":{"accession":"P48728","full_name":"Aminomethyltransferase, mitochondrial","aliases":["Glycine cleavage system T protein","GCVT"],"length_aa":403,"mass_kda":43.9,"function":"The glycine cleavage system catalyzes the degradation of glycine","subcellular_location":"Mitochondrion","url":"https://www.uniprot.org/uniprotkb/P48728/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/AMT","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/AMT","total_profiled":1310},"omim":[{"mim_id":"620398","title":"GLYCINE ENCEPHALOPATHY 2; GCE2","url":"https://www.omim.org/entry/620398"},{"mim_id":"610516","title":"GLYCERATE KINASE; GLYCTK","url":"https://www.omim.org/entry/610516"},{"mim_id":"607079","title":"RHESUS BLOOD GROUP, B GLYCOPROTEIN; RHBG","url":"https://www.omim.org/entry/607079"},{"mim_id":"605899","title":"GLYCINE ENCEPHALOPATHY 1; GCE1","url":"https://www.omim.org/entry/605899"},{"mim_id":"605381","title":"RHESUS BLOOD GROUP, C GLYCOPROTEIN; RHCG","url":"https://www.omim.org/entry/605381"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"liver","ntpm":52.5}],"url":"https://www.proteinatlas.org/search/AMT"},"hgnc":{"alias_symbol":["GCST","NKH"],"prev_symbol":[]},"alphafold":{"accession":"P48728","domains":[{"cath_id":"3.30.1360.120","chopping":"37-82_177-266","consensus_level":"high","plddt":98.561,"start":37,"end":266},{"cath_id":"3.30.70.1400","chopping":"84-176_282-316","consensus_level":"medium","plddt":98.2776,"start":84,"end":316},{"cath_id":"2.40.30.110","chopping":"318-393","consensus_level":"medium","plddt":98.2618,"start":318,"end":393}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P48728","model_url":"https://alphafold.ebi.ac.uk/files/AF-P48728-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P48728-F1-predicted_aligned_error_v6.png","plddt_mean":93.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=AMT","jax_strain_url":"https://www.jax.org/strain/search?query=AMT"},"sequence":{"accession":"P48728","fasta_url":"https://rest.uniprot.org/uniprotkb/P48728.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P48728/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P48728"}},"corpus_meta":[{"pmid":"3086432","id":"PMC_3086432","title":"The relationship of CD16 (Leu-11) and Leu-19 (NKH-1) antigen expression on human peripheral blood NK cells and cytotoxic T lymphocytes.","date":"1986","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/3086432","citation_count":1095,"is_preprint":false},{"pmid":"15361618","id":"PMC_15361618","title":"Mechanism of ammonia transport by Amt/MEP/Rh: structure of AmtB at 1.35 A.","date":"2004","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/15361618","citation_count":516,"is_preprint":false},{"pmid":"1695113","id":"PMC_1695113","title":"Plasma cells in multiple myeloma express a natural killer cell-associated antigen: CD56 (NKH-1; 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AMT mutations were found in 11 of 69 families, distinct from GLDC mutations.\",\n      \"method\": \"Complete coding-region sequencing of AMT, GLDC, and GCSH in NKH patient cohort; mutation characterization\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — large cohort sequencing with systematic mutation identification, replicated across multiple families and labs\",\n      \"pmids\": [\"16450403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Recurring mutations in the AMT (T-protein) gene were identified in NKH patients: R320H (7% of alleles) and a splice site mutation IVS7-1G>A (3% of alleles), with a novel point mutation N145I also described, establishing AMT as encoding the glycine cleavage T-protein whose loss of function causes NKH.\",\n      \"method\": \"DNA sequencing, PCR/restriction enzyme assays, allele frequency screening in NKH patient bank\",\n      \"journal\": \"Molecular genetics and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — systematic mutation screening across patient cohort, single lab\",\n      \"pmids\": [\"11286506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The first splice site mutation in the AMT gene (IVS7-1G→A) was identified in three unrelated NKH families, confirming AMT encodes the glycine cleavage T-protein and that splice-site loss of function mutations in AMT cause NKH.\",\n      \"method\": \"PCR/restriction enzyme mutation screening of 100 NKH alleles; Sanger sequencing\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutation identified across multiple unrelated families, functionally consistent with NKH phenotype\",\n      \"pmids\": [\"11139253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The murine Amt gene was cloned and sequenced, shown to consist of nine closely spaced exons within ~5 kb of genomic DNA encoding a 403-amino acid protein highly homologous to human aminomethyltransferase, with the Nicolin 1 gene (Nicn1) immediately upstream.\",\n      \"method\": \"Genomic cloning, sequencing, exon-intron mapping\",\n      \"journal\": \"DNA sequence\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct structural characterization of the orthologous murine gene\",\n      \"pmids\": [\"12487019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The canine AMT gene was mapped to chromosome 20q15.1→q15.2, shown to span 5 kb with nine exons, encoding a 403-amino acid protein with 88% identity to human aminomethyltransferase, closely linked to the TCTA gene.\",\n      \"method\": \"Genomic sequence analysis, gene mapping, sequence alignment\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct genomic structural characterization of canine ortholog\",\n      \"pmids\": [\"10894947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"In NKH patients with unusual biochemical findings (residual glycine cleavage activity in liver or lymphoblasts, or abnormal amniotic fluid glycine/serine ratio with normal glycine), T-protein (AMT) defects accounted for >50% of cases, with novel AMT mutations identified (including R296H), establishing that AMT mutations can produce residual enzyme activity and atypical NKH presentations.\",\n      \"method\": \"Enzyme activity assays in liver and lymphoblasts, sequencing, PCR/restriction enzyme methods\",\n      \"journal\": \"Molecular genetics and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional enzyme assays combined with mutation identification in patient cohort\",\n      \"pmids\": [\"12948742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Analysis of 578 NKH families identified 410 unique mutations; AMT mutations (primarily missense, often recurring) were identified with biallelic pathogenic variants in 98% of AMT-affected subjects. Genotype in AMT correlated with attenuated vs. classic NKH phenotype in 15% of subjects.\",\n      \"method\": \"Sequencing, CNV analysis, genotype-phenotype correlation across large international cohort\",\n      \"journal\": \"Genetics in medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — large multi-center cohort with systematic mutation identification and genotype-phenotype correlation\",\n      \"pmids\": [\"27362913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Novel compound heterozygous frameshift mutations in AMT exon 8 (c.977delA and c.982_983insG) were identified by whole-exome sequencing in a Chinese NKH patient, inherited from each parent, confirming autosomal recessive inheritance of AMT-related NKH.\",\n      \"method\": \"Whole-exome sequencing, Sanger sequencing validation, family segregation analysis\",\n      \"journal\": \"Frontiers in genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — WES with Sanger validation and family segregation, single case\",\n      \"pmids\": [\"35646099\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Human AMT encodes aminomethyltransferase (T-protein), a component of the mitochondrial glycine cleavage system (EC 2.1.2.10) whose loss-of-function mutations—missense, frameshift, or splice-site, inherited in an autosomal recessive manner—cause nonketotic hyperglycinemia (NKH) by impairing glycine catabolism; the gene spans ~6 kb with nine exons at chromosomal locus 3p21.2-p21.1, and residual AMT enzyme activity correlates with attenuated clinical phenotypes.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"AMT encodes aminomethyltransferase (T-protein), a mitochondrial enzyme of the glycine cleavage system that catalyzes the transfer of the aminomethyl moiety from the H-protein lipoyl arm to tetrahydrofolate, yielding 5,10-methylene-tetrahydrofolate and ammonia as part of glycine catabolism [PMID:8188235]. The human AMT gene spans approximately 6 kb with nine exons at chromosome 3p21.2-p21.1 and encodes a protein highly conserved across mammals [PMID:8188235, PMID:10894947]. Biallelic loss-of-function mutations in AMT—predominantly missense but also frameshift and splice-site variants—cause nonketotic hyperglycinemia (NKH), with residual AMT enzyme activity correlating with attenuated rather than classic disease presentation [PMID:16450403, PMID:27362913, PMID:12948742].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Establishing the genomic structure and chromosomal location of human AMT resolved the gene architecture encoding the glycine cleavage T-protein, enabling subsequent mutation screening in NKH patients.\",\n      \"evidence\": \"Genomic library screening, restriction mapping, sequencing, primer extension, and FISH mapping to 3p21.2-p21.1\",\n      \"pmids\": [\"8188235\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No disease-causing mutations identified at this stage\",\n        \"Promoter elements described computationally but not functionally validated\",\n        \"No crystal structure of the human protein\"\n      ]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Characterization of canine and murine AMT orthologs demonstrated high sequence conservation (88% identity to human) and identical nine-exon gene architecture, supporting functional conservation of aminomethyltransferase across mammals.\",\n      \"evidence\": \"Genomic cloning, sequencing, and gene mapping of canine (chr 20q15.1–q15.2) and murine Amt genes\",\n      \"pmids\": [\"10894947\", \"12487019\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No functional assays performed in animal models to test enzymatic equivalence\",\n        \"No animal model of AMT deficiency generated\"\n      ]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identification of recurring AMT mutations (R320H, IVS7-1G>A) in unrelated NKH families established that loss of T-protein function directly causes nonketotic hyperglycinemia, distinguishing AMT-related NKH from GLDC-related NKH.\",\n      \"evidence\": \"Sanger sequencing and PCR/restriction enzyme screening across NKH patient cohorts from multiple unrelated families\",\n      \"pmids\": [\"11286506\", \"11139253\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional impact of individual mutations not demonstrated by in vitro enzyme assays\",\n        \"Relative contribution of AMT vs. GLDC mutations to NKH prevalence not yet quantified in large cohorts\"\n      ]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrating that AMT mutations can produce residual glycine cleavage activity and atypical NKH presentations revealed that AMT genotype modulates disease severity, not just presence or absence of disease.\",\n      \"evidence\": \"Enzyme activity assays in liver and lymphoblasts combined with mutation identification in patients with unusual biochemical profiles\",\n      \"pmids\": [\"12948742\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Structural basis for why specific mutations retain partial activity unknown\",\n        \"No recombinant expression system used to quantify individual mutant enzyme kinetics\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Systematic sequencing of all three glycine cleavage genes across 69 NKH families quantified AMT mutations as the cause in ~16% of families, with missense mutations predominating, delineating the genetic landscape of AMT-related NKH.\",\n      \"evidence\": \"Complete coding-region sequencing of AMT, GLDC, and GCSH in a 69-family NKH cohort\",\n      \"pmids\": [\"16450403\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Deep intronic and regulatory variants not assessed\",\n        \"No functional validation of newly identified missense variants\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Large-scale international genotype-phenotype analysis across 578 NKH families confirmed that AMT genotype predicts attenuated vs. classic NKH in a subset of patients, solidifying the correlation between residual T-protein function and clinical outcome.\",\n      \"evidence\": \"Sequencing and CNV analysis with phenotype correlation in a multi-center cohort of 578 families\",\n      \"pmids\": [\"27362913\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which specific AMT genotypes produce residual activity not structurally resolved\",\n        \"No therapeutic strategies targeting residual AMT activity tested\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Discovery of novel compound heterozygous frameshift mutations in a Chinese NKH patient expanded the AMT mutational spectrum and confirmed autosomal recessive inheritance in a previously underrepresented population.\",\n      \"evidence\": \"Whole-exome sequencing with Sanger validation and family segregation analysis\",\n      \"pmids\": [\"35646099\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single case report; population frequency of these alleles unknown\",\n        \"No functional assay of the truncated proteins\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis for differential residual activity of AMT missense variants, the precise mechanism of AMT's interaction with H-protein within the glycine cleavage complex, and whether pharmacological chaperones or gene therapy can rescue partial AMT deficiency remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structure of human AMT in complex with H-protein\",\n        \"No reconstituted in vitro system measuring kinetics of individual disease-causing mutants\",\n        \"No animal model of AMT-deficient NKH established for therapeutic testing\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1, 6, 7]}\n    ],\n    \"complexes\": [\"glycine cleavage system\"],\n    \"partners\": [\"GLDC\", \"GCSH\"],\n    \"other_free_text\": []\n  }\n}\n```"}