{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/b0f1905b-b918-4f3d-95b4-0ffeb33d2386/doc/sepio/version/1.0.0", "assertionMethod": { "type": "VariantPathogenicityInterpretationGuideline" }, "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/CA6748732/MONDO:0009861/006/el/0/1669", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6748732/MONDO:0009861/006/ei/1/1670", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50015_EP155190578201949", "id": "CG-PCER-AGENT:CG_50015_EP155190578201949", "type": "Agent" }, "contributionDate": { "date": "2019/10/18", "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" } ], "criterion": { "@id": "https://obofoundry.org/sepio/clingen/0038", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000220", "id": "SEPIO:0000220", "label": "Pathogenic Very Strong" }, "id": "0038", "label": "PM3", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6748732/MONDO:0009861/006/el/0/1669/1671", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA6748732/MONDO:0009861/006/ci/EV000000028", "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 was detected in trans with the pathogenic PAH variant Arg408Gln in 1 patient with mild hyperphenylalaninemia. Parental analysis was not performed to confirm compound heterozygosity. This variant was documented in a 2nd patient diagnosed with mild hyperphenylalaninemia (MHP), however, the variant in trans was not specified.", "contributionDate": { "date": "2019/10/18", "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": "CA6748732/MONDO:0009861/006/ci/EV000000028", "traceableAuthorStatement": "https://www.ncbi.nlm.nih.gov/pubmed/24401910", "type": "CuratorInference" }, { "@id": "CG-PCER:curatorInference/CA6748732/MONDO:0009861/006/ci/EV000000778", "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 was detected in trans with the pathogenic variant p.Tyr356* in 2 patients, one was diagnosed with mild hyperphenylalaninemia and the 2nd was diagnosed with classic PKU. This variant was detected in trans with the pathogenic variant p.Arg243Gln in a patient diagnosed with mild hyperphenylalaninemia. This variant was detected in trans with the pathogenic variant p.Ser70del in a patient diagnosed with mild hyperphenylalaninemia. This variant was detected in a second patient diagnosed with classical PKU, however the variant in trans was not reported. Parental analysis was performed to confirm compound heterozygosity.", "contributionDate": { "date": "2019/10/18", "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": "CA6748732/MONDO:0009861/006/ci/EV000000778", "traceableAuthorStatement": "https://www.ncbi.nlm.nih.gov/pubmed/29316886", "type": "CuratorInference" }, { "@id": "CG-PCER:curatorInference/CA6748732/MONDO:0009861/006/ci/EV000000777", "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 was documented in one patient with mild hyperphenylalaninemia with the pathogenic variant c.331C>T (p.Arg111Ter) in trans. Parental analysis was not performed to confirm compound heterozygosity.", "contributionDate": { "date": "2019/10/18", "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": "CA6748732/MONDO:0009861/006/ci/EV000000777", "traceableAuthorStatement": "https://www.ncbi.nlm.nih.gov/pubmed/31445982", "type": "CuratorInference" }, { "@id": "CG-PCER:curatorInference/CA6748732/MONDO:0009861/006/ci/EV000000510", "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 was documented in 7 Chinese patients diagnosed with mild hyperphenylalaninemia. The reported variant in trans for each of the patients was the pathogenic variant c.1197A>T (in 2 patients), the pathogenic variant c.728G>A (p.Arg243Gln) (in 1 patient), the pathogenic variant c.721C>T (in 1 patient), the VUS c.1099C>G (in 1 patient), c.763T>G (in 1 patient), and c.460T>C (in 1 patient). Parental analysis was performed to confirm compound heterozygosity.", "contributionDate": { "date": "2019/10/18", "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": "CA6748732/MONDO:0009861/006/ci/EV000000510", "traceableAuthorStatement": "https://www.ncbi.nlm.nih.gov/pubmed/30050108", "type": "CuratorInference" } ], "id": "CG-PCER-VARINT:CA6748732/MONDO:0009861/006/0/1669/1671", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA6748732/MONDO:0009861/006/1/1670", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA6748732/MONDO:0009861/006/0/1669", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6748732/MONDO:0009861/006/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6748732/MONDO:0009861/006/ei/1/1748", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50015_EP155190578201949", "id": "CG-PCER-AGENT:CG_50015_EP155190578201949", "type": "Agent" }, "contributionDate": { "date": "2019/10/18", "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" } ], "criterion": { "@id": "https://obofoundry.org/sepio/clingen/0062", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000329", "id": "SEPIO:0000329", "label": "Pathogenic Supporting" }, "id": "0062", "label": "PP3", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6748732/MONDO:0009861/006/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA6748732/MONDO:0009861/006/ci/CA6748732/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": "Predicted to be damaging (SIFT), probably damaging (PolyPhen2), Disease causing (MutationTaster)", "contributionDate": { "date": "2019/10/18", "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": "CA6748732/MONDO:0009861/006/ci/CA6748732/MONDO:0009861/006.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA6748732/MONDO:0009861/006/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA6748732/MONDO:0009861/006/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA6748732/MONDO:0009861/006/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6748732/MONDO:0009861/006/el/0/1798", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6748732/MONDO:0009861/006/ei/1/1799", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50015_EP155190578201949", "id": "CG-PCER-AGENT:CG_50015_EP155190578201949", "type": "Agent" }, "contributionDate": { "date": "2019/10/18", "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" } ], "criterion": { "@id": "https://obofoundry.org/sepio/clingen/0011", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000216", "id": "SEPIO:0000216", "label": "Pathogenic Moderate" }, "id": "0011", "label": "PM2", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6748732/MONDO:0009861/006/el/0/1798/1800", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA6748732/MONDO:0009861/006/ci/CA6748732/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": "Present in East Asian populations at frequency of 0.00198 and in all populations at frequency of 0.00040 (1000 Genomes). The PM2 threshold set by the PAH Variant Curation Expert Panel (VCEP) is 0.0002.", "contributionDate": { "date": "2019/10/18", "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": "CA6748732/MONDO:0009861/006/ci/CA6748732/MONDO:0009861/006.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA6748732/MONDO:0009861/006/0/1798/1800", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA6748732/MONDO:0009861/006/1/1799", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA6748732/MONDO:0009861/006/0/1798", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6748732/MONDO:0009861/006/el/0/1831", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6748732/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": "2019/10/18", "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" } ], "criterion": { "@id": "https://obofoundry.org/sepio/clingen/0018", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000216", "id": "SEPIO:0000216", "label": "Pathogenic Moderate" }, "id": "0018", "label": "PP4", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6748732/MONDO:0009861/006/el/0/1831/1833", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA6748732/MONDO:0009861/006/ci/EV000000041", "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 was documented three times in Southern Chinese patients and three times in Northern Chinese patients with PAH deficiency (PMID: 26503515). It was not specified whether patient genotypes were homozygous or compound heterozygous for the variant. Subjects in this study were diagnosed through neonatal screening program or by clinical presentation. Phenylalanine plasma concentrations >120 µmol/L were reported for all subjects. Tetrahydrobiopterin (BH4) deficiency was excluded through a BH4 loading test, urinary pterin analysis, and DHPR activity assay.", "contributionDate": { "date": "2019/10/18", "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": "CA6748732/MONDO:0009861/006/ci/EV000000041", "traceableAuthorStatement": "https://www.ncbi.nlm.nih.gov/pubmed/26503515", "type": "CuratorInference" }, { "@id": "CG-PCER:curatorInference/CA6748732/MONDO:0009861/006/ci/EV000000776", "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 was documented 7 times in mild hyperphenylalaninemia (Phe value of <360 µmol/L) patients from Zhejiang Province. It was not specified whether patient genotypes were homozygous or compound heterozygous for the variant.", "contributionDate": { "date": "2019/10/18", "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": "CA6748732/MONDO:0009861/006/ci/EV000000776", "traceableAuthorStatement": "https://www.ncbi.nlm.nih.gov/pubmed/30459323", "type": "CuratorInference" }, { "@id": "CG-PCER:curatorInference/CA6748732/MONDO:0009861/006/ci/EV000000301", "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 was documented in trans with the VUS p.L367V in 1 patient diagnosed with mild hyperphenylalaninemia.", "contributionDate": { "date": "2019/10/18", "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": "CA6748732/MONDO:0009861/006/ci/EV000000301", "traceableAuthorStatement": "https://www.ncbi.nlm.nih.gov/pubmed/26322415", "type": "CuratorInference" }, { "@id": "CG-PCER:curatorInference/CA6748732/MONDO:0009861/006/ci/EV000000700", "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 was documented 5 times in patients diagnosed with mild hyperphenylalaninemia (MHP) in Northwest China. It was not specified whether patient genotypes were homozygous or compound heterozygous for the variant.", "contributionDate": { "date": "2019/10/18", "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": "CA6748732/MONDO:0009861/006/ci/EV000000700", "traceableAuthorStatement": "https://www.ncbi.nlm.nih.gov/pubmed/30747360", "type": "CuratorInference" } ], "id": "CG-PCER-VARINT:CA6748732/MONDO:0009861/006/0/1831/1833", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA6748732/MONDO:0009861/006/1/1832", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA6748732/MONDO:0009861/006/0/1831", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA6748732/MONDO:0009861/006", "metadata": { "created": "2024-09-27T20:10:38.767Z", "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, 27 Sep 2024 20:10:38 -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": "b0f1905b-b918-4f3d-95b4-0ffeb33d2386", "variant": { "@id": "https://reg.genome.network/allele/CA6748732", "id": "CAR:CA6748732", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000277.3:c.1174T>A" } ], "preferred": true } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-11-05T10:29:22.969Z" } }, "status": { "code": 200, "name": "OK" } }