{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/e90820bd-3677-45f6-9940-20fe8af192fa/doc/sepio/version/1.0.0", "assertionMethod": { "@id": "https://cspec.genome.network/cspec/SequenceVariantInterpretation/id/135637578", "label": "ClinGen Phenylketonuria Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PAH Version 2.0.0", "type": "VariantPathogenicityInterpretationGuideline", "version": "2.0.0" }, "condition": { "@id": "https://api.monarchinitiative.org/api/bioentity/phenotype/MONDO:0009861", "id": "MONDO:0009861", "label": "phenylketonuria", "type": "GeneticCondition" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA229373/MONDO:0009861/006/el/0/1651", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA229373/MONDO:0009861/006/ei/1/1652", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50015_EP155190578201949", "id": "CG-PCER-AGENT:CG_50015_EP155190578201949", "type": "Agent" }, "contributionDate": { "date": "2025/8/15", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA229373/MONDO:0009861/006/el/0/1651/1653", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA229373/MONDO:0009861/006/ci/CA229373/MONDO:0009861/006.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50015_EP155190578201949", "id": "CG-PCER-AGENT:CG_50015_EP155190578201949", "type": "Agent" }, "comments": "This variant has been detected in at least 5 individuals with Phenylketonuria. All individuals were compound heterozygous for the variant and distinct pathogenic variants in unknown phase (PM3_strong, PMIDs: 17502162, 12836060, 11999982, 7726156). ", "contributionDate": { "date": "2025/8/15", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "id": "CA229373/MONDO:0009861/006/ci/CA229373/MONDO:0009861/006.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA229373/MONDO:0009861/006/0/1651/1653", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA229373/MONDO:0009861/006/1/1652", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA229373/MONDO:0009861/006/0/1651", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA229373/MONDO:0009861/006/el/0/1696", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA229373/MONDO:0009861/006/ei/1/1697", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50015_EP155190578201949", "id": "CG-PCER-AGENT:CG_50015_EP155190578201949", "type": "Agent" }, "contributionDate": { "date": "2025/8/15", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA229373/MONDO:0009861/006/el/0/1696/1698", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA229373/MONDO:0009861/006/ci/EV000000051", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50015_EP155190578201949", "id": "CG-PCER-AGENT:CG_50015_EP155190578201949", "type": "Agent" }, "comments": "A395P mutant PAH enzyme activity 17;14 % wt (pcDNA3/IVT) and 15 +/- 7 (pET/E. coli). We have used two heterologous in vitro expression systems (cell-free rabbit reticulocyte lysates and the pET system of E. coli) to assess the residual\nactivities and oligomeric compositions of 34 missense variants associated with PAH deficiency in the Danish and other populations. To allow direct comparisons\nbetween different mutant enzymes, our approach was designed to analyze all mutations synchronously under identical experimental conditions. Total protein concentrations were standardized to 6 mg/ml. Included negative vector control.", "contributionDate": { "date": "2025/8/15", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "id": "CA229373/MONDO:0009861/006/ci/EV000000051", "traceableAuthorStatement": "https://www.ncbi.nlm.nih.gov/pubmed/11161839", "type": "CuratorInference" } ], "id": "CG-PCER-VARINT:CA229373/MONDO:0009861/006/0/1696/1698", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA229373/MONDO:0009861/006/1/1697", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA229373/MONDO:0009861/006/0/1696", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA229373/MONDO:0009861/006/el/0/1831", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA229373/MONDO:0009861/006/ei/1/1832", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50015_EP155190578201949", "id": "CG-PCER-AGENT:CG_50015_EP155190578201949", "type": "Agent" }, "contributionDate": { "date": "2025/8/15", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA229373/MONDO:0009861/006/el/0/1831/1833", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA229373/MONDO:0009861/006/ci/EV000000008", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50015_EP155190578201949", "id": "CG-PCER-AGENT:CG_50015_EP155190578201949", "type": "Agent" }, "comments": "PMID 9634518: excluded BH4 deficiency. In two patients, classified p.Ala395Pro as classic PKU variant.", "contributionDate": { "date": "2025/8/15", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "id": "CA229373/MONDO:0009861/006/ci/EV000000008", "traceableAuthorStatement": "https://www.ncbi.nlm.nih.gov/pubmed/9634518", "type": "CuratorInference" } ], "id": "CG-PCER-VARINT:CA229373/MONDO:0009861/006/0/1831/1833", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA229373/MONDO:0009861/006/1/1832", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA229373/MONDO:0009861/006/0/1831", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA229373/MONDO:0009861/006/el/0/1753", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA229373/MONDO:0009861/006/ei/1/1754", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50015_EP155190578201949", "id": "CG-PCER-AGENT:CG_50015_EP155190578201949", "type": "Agent" }, "contributionDate": { "date": "2025/8/15", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA229373/MONDO:0009861/006/el/0/1753/1755", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA229373/MONDO:0009861/006/ci/CA229373/MONDO:0009861/006.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50015_EP155190578201949", "id": "CG-PCER-AGENT:CG_50015_EP155190578201949", "type": "Agent" }, "comments": "The computational predictor REVEL gives a score of 0.988, which meets the threshold of 0.932, evidence that correlates with strong impact to PAH function (PP3_Strong).", "contributionDate": { "date": "2025/8/15", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "id": "CA229373/MONDO:0009861/006/ci/CA229373/MONDO:0009861/006.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA229373/MONDO:0009861/006/0/1753/1755", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA229373/MONDO:0009861/006/1/1754", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA229373/MONDO:0009861/006/0/1753", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA229373/MONDO:0009861/006/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA229373/MONDO:0009861/006/ei/1/1637", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50015_EP155190578201949", "id": "CG-PCER-AGENT:CG_50015_EP155190578201949", "type": "Agent" }, "contributionDate": { "date": "2025/8/15", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA229373/MONDO:0009861/006/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA229373/MONDO:0009861/006/ci/CA229373/MONDO:0009861/006.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50015_EP155190578201949", "id": "CG-PCER-AGENT:CG_50015_EP155190578201949", "type": "Agent" }, "comments": "The highest population minor allele frequency in gnomAD v4.1.0 is 0.00001017 in European (non-Finnish), which is lower than the ClinGen PAH Variant Curation Expert Panel threshold (<0.0002) for PM2_Supporting, meeting this criterion (PM2_Supporting).", "contributionDate": { "date": "2025/8/15", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "id": "CA229373/MONDO:0009861/006/ci/CA229373/MONDO:0009861/006.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA229373/MONDO:0009861/006/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA229373/MONDO:0009861/006/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA229373/MONDO:0009861/006/0/1636", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA229373/MONDO:0009861/006", "metadata": { "created": "2025-08-15T15:42:05.416Z", "note": "DISCLAIMER: While the data/content in this document is approved by ClinGen expert panel(s), the SEPIO schema presented here is an initial prototype and has not been reviewed nor finalized by the ClinGen Data Exchange Modeling Team. We expect it to differ significantly from the final schema.", "producedAtUTC": "Fri, 15 Aug 2025 15:42:05 -0000", "schemaLabel": "Evidence Repository.Beta-1 (Unofficial)", "version": "1.0.0" }, "statementOutcome": { "@id": "https://loinc.org/LA6668-3", "id": "LN:LA6668-3", "label": "Pathogenic" }, "type": "VariantPathogenicityInterpretation", "uuid": "e90820bd-3677-45f6-9940-20fe8af192fa", "variant": { "@id": "https://reg.genome.network/allele/CA229373", "id": "CAR:CA229373", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000277.1:c.1183G>C" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000277.1(PAH):c.1183G>C (p.Ala395Pro)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-11-01T05:35:05.800Z" } }, "status": { "code": 200, "name": "OK" } }