{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/69793eba-f1b8-4e7f-af42-b3a459a72236/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/CA16020997/MONDO:0009861/006/el/0/1762", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA16020997/MONDO:0009861/006/ei/1/1763", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50015_EP155190578201949", "id": "CG-PCER-AGENT:CG_50015_EP155190578201949", "type": "Agent" }, "contributionDate": { "date": "2020/5/15", "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" } ], "criterion": { "@id": "https://obofoundry.org/sepio/clingen/0020", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000330", "id": "SEPIO:0000330", "label": "Pathogenic Strong" }, "id": "0020", "label": "PVS1", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA16020997/MONDO:0009861/006/el/0/1762/1764", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA16020997/MONDO:0009861/006/ci/CA16020997/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 c.1318G>T (p.E440*) is a nonsense variant in exon 13 of 13 of PAH, a gene where loss of function is a known disease mechanism, and is predicted to lead to premature truncation of the protein at amino acid 440/453 (PVS1_Strong). Exon 13 encodes 15 amino acids + stop codon = 3.3% of PAH protein length. Along with Exon 12, Exon 13 forms the oligomerization domain (residues 411–452), which is responsible for the dimerization and tetramerization of the enzyme, important for regulation of PAH activity (e.g., positive cooperativity by the substrate, L-Phe, and decreasing PAH activity at low L-Phe concentration) (see PMID: 23457044; PMID: 22005392). Exon 13 contains the non-truncating Likely Pathogenic p.A447P (Likely Pathogenic by ClinGen PAH VCEP) and Pathogenic p.A447D variants (Likely Pathogenic by ClinGen PAH VCEP; Pathogenic in Clinvar (ID 102595; 4 submitters, 2 stars). Thus PVS1_Strong will be applied for variants resulting in premature truncation of this exon", "contributionDate": { "date": "2020/5/15", "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": "CA16020997/MONDO:0009861/006/ci/CA16020997/MONDO:0009861/006.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA16020997/MONDO:0009861/006/0/1762/1764", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA16020997/MONDO:0009861/006/1/1763", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA16020997/MONDO:0009861/006/0/1762", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA16020997/MONDO:0009861/006/el/0/1609", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA16020997/MONDO:0009861/006/ei/1/1610", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50015_EP155190578201949", "id": "CG-PCER-AGENT:CG_50015_EP155190578201949", "type": "Agent" }, "contributionDate": { "date": "2020/5/15", "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" } ], "criterion": { "@id": "https://obofoundry.org/sepio/clingen/0027", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000329", "id": "SEPIO:0000329", "label": "Pathogenic Supporting" }, "id": "0027", "label": "PM3", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA16020997/MONDO:0009861/006/el/0/1609/1611", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA16020997/MONDO:0009861/006/ci/CA16020997/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": "(PMID: 23842451) in presumed trans with the p.R243* mutation (Pathogenic per PAH VCEP) (0.5 points; PM3_Supporting).", "contributionDate": { "date": "2020/5/15", "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": "CA16020997/MONDO:0009861/006/ci/CA16020997/MONDO:0009861/006.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA16020997/MONDO:0009861/006/0/1609/1611", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA16020997/MONDO:0009861/006/1/1610", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA16020997/MONDO:0009861/006/0/1609", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA16020997/MONDO:0009861/006/el/0/1798", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA16020997/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": "2020/5/15", "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" } ], "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/CA16020997/MONDO:0009861/006/el/0/1798/1800", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA16020997/MONDO:0009861/006/ci/CA16020997/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 variant is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2).", "contributionDate": { "date": "2020/5/15", "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": "CA16020997/MONDO:0009861/006/ci/CA16020997/MONDO:0009861/006.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA16020997/MONDO:0009861/006/0/1798/1800", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA16020997/MONDO:0009861/006/1/1799", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA16020997/MONDO:0009861/006/0/1798", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA16020997/MONDO:0009861/006/el/0/1633", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA16020997/MONDO:0009861/006/ei/1/1634", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50015_EP155190578201949", "id": "CG-PCER-AGENT:CG_50015_EP155190578201949", "type": "Agent" }, "contributionDate": { "date": "2020/5/15", "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" } ], "criterion": { "@id": "https://obofoundry.org/sepio/clingen/0063", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000329", "id": "SEPIO:0000329", "label": "Pathogenic Supporting" }, "id": "0063", "label": "PP4", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA16020997/MONDO:0009861/006/el/0/1633/1635", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA16020997/MONDO:0009861/006/ci/CA16020997/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": "It has been previously reported in one proband with abnormal blood Phe (BH4 deficiency does not appear to have been formally excluded) (PP4) (PMID: 23842451), in presumed trans with the p.R243* mutation (Pathogenic per PAH VCEP) (0.5 points; PM3_Supporting).", "contributionDate": { "date": "2020/5/15", "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": "CA16020997/MONDO:0009861/006/ci/CA16020997/MONDO:0009861/006.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA16020997/MONDO:0009861/006/0/1633/1635", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA16020997/MONDO:0009861/006/1/1634", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA16020997/MONDO:0009861/006/0/1633", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA16020997/MONDO:0009861/006", "metadata": { "created": "2024-09-27T20:44:56.130Z", "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 20:44:56 -0000", "schemaLabel": "Evidence Repository.Beta-1 (Unofficial)", "version": "1.0.0" }, "statementOutcome": { "@id": "https://loinc.org/LA26332-9", "id": "LN:LA26332-9", "label": "Likely Pathogenic" }, "type": "VariantPathogenicityInterpretation", "uuid": "69793eba-f1b8-4e7f-af42-b3a459a72236", "variant": { "@id": "https://reg.genome.network/allele/CA16020997", "id": "CAR:CA16020997", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_001354304.2:c.1318G>T" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_001354304.2:c.1318G>T" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-10-30T04:33:37.849Z" } }, "status": { "code": 200, "name": "OK" } }