{"id":"52ef8028-761d-564c-a2f4-48664bfeaaa3","stable_key":"911fb3c7-8cc3-5667-b677-5682fab67648:histidine-hars-variant","predicate":"impairs_tested","statement":"HARS1 Arg137Gln identified in a neuropathy screen showed loss of function in yeast complementation and neuronal toxicity in a worm expression model.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"context_dependent","is_public":true,"mechanism_event_id":"416830d5-fa0f-59e6-b2d6-0da8dc6183bb","mechanism_event_label":"A defective histidine-using enzyme can cause cellular problems that substrate alone has not been shown to fix.","subject":{"id":"62cdd43c-a884-5300-b331-d04832eb9b97","slug":"human-hars1-r137q","display_name":"Human HARS1 Arg137Gln variant","entity_type_key":"cellular_process"},"object":{"id":"639ed1bf-e69f-5e4f-b5b1-279638b21bec","slug":"hars1","display_name":"Human cytosolic histidyl-tRNA synthetase / HARS1","entity_type_key":"protein"},"evidence_count":1,"mechanism_event":{"id":"416830d5-fa0f-59e6-b2d6-0da8dc6183bb","stable_key":"911fb3c7-8cc3-5667-b677-5682fab67648:histidine-hars-variant-event","event_type":"observed_relationship","label":"A defective histidine-using enzyme can cause cellular problems that substrate alone has not been shown to fix.","description":"HARS1 Arg137Gln identified in a neuropathy screen showed loss of function in yeast complementation and neuronal toxicity in a worm expression model.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"62cdd43c-a884-5300-b331-d04832eb9b97","slug":"human-hars1-r137q","display_name":"Human HARS1 Arg137Gln variant","entity_type_key":"cellular_process"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"639ed1bf-e69f-5e4f-b5b1-279638b21bec","slug":"hars1","display_name":"Human cytosolic histidyl-tRNA synthetase / HARS1","entity_type_key":"protein"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"44374451-3436-5136-a8ae-5dcc6d8c353b","slug":"histidine","display_name":"L-Histidine","entity_type_key":"small_molecule"},"role":"context_participant","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""}]},"contexts":[{"dimension":"availability_state","value_text":"machinery_impairment","comparator":null,"unit":null,"notes":"Imported condition classification; unverified.","entity":null},{"dimension":"evidence_access","value_text":"Primary full text","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Human variant discovery, orthologous yeast complementation and C. elegans functional assays.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"The variant also occurred in additional sequenced people; functional findings do not establish penetrance or an effective histidine treatment.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"L-Histidine collection; species, compartment, exposure, co-substrates and manipulation remain explicit.","comparator":null,"unit":null,"notes":"","entity":{"slug":"histidine","display_name":"L-Histidine","entity_type_key":"small_molecule"}},{"dimension":"plain_language","value_text":"A defective histidine-using enzyme can cause cellular problems that substrate alone has not been shown to fix.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"A loss-of-function variant in the human histidyl-tRNA synthetase (HARS) gene is neurotoxic in vivo. · 2013 · https://pubmed.ncbi.nlm.nih.gov/22930593/ · DOI 10.1002/humu.22210","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"trigger_kind","value_text":"machinery_impairment","comparator":null,"unit":null,"notes":"Imported condition classification; unverified.","entity":null}],"evidence":[{"id":"e1ad217c-ebd8-5453-a93d-4e2703bb4b72","evidence_kind":"source_excerpt","locator":"Lines 466-472","start_line":466,"end_line":472,"excerpt":"## histidine-hars-variant\nA defective histidine-using enzyme can cause cellular problems that substrate alone has not been shown to fix.\nHARS1 Arg137Gln identified in a neuropathy screen showed loss of function in yeast complementation and neuronal toxicity in a worm expression model.\nModel: Human variant discovery, orthologous yeast complementation and C. elegans functional assays.\nLimitations: The variant also occurred in additional sequenced people; functional findings do not establish penetrance or an effective histidine treatment.\nEvidence access: Primary full text\nA loss-of-function variant in the human histidyl-tRNA synthetase (HARS) gene is neurotoxic in vivo. · 2013 · https://pubmed.ncbi.nlm.nih.gov/22930593/ · DOI 10.1002/humu.22210","model_system":"Human variant discovery, orthologous yeast complementation and C. elegans functional assays.","directness":"reported_statement","verification_status":"source_derived_draft","notes":"Original curation paraphrase; 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