{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/00b68297-2f63-4952-bc0d-108c6dfecefb/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/CA281520/MONDO:0009861/006/el/0/1696", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA281520/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": "2021/2/11", "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/0045", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000329", "id": "SEPIO:0000329", "label": "Pathogenic Supporting" }, "id": "0045", "label": "PS3", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA281520/MONDO:0009861/006/el/0/1696/1698", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA281520/MONDO:0009861/006/ci/EV000001263", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50015_EP155190578201949", "id": "CG-PCER-AGENT:CG_50015_EP155190578201949", "type": "Agent" }, "comments": "The –4173_-407del mutation diminishes PAH gene expression. CAT activities were compared between constructs carrying the basic PAH promoter (Fig. 6, construct A) and the 5′ 9-kb PAH sequence (construct B) and its derivatives, including one with the –4173_-407del mutation (construct C) or the deletion of the liver-specific enhancer (construct D). Furthermore, the –4173_-407del mutation (construct C)\nretained only 1% of the wild-type CAT activity suggesting that, in addition to the liver-specific enhancer, there are other cis-elements that lie within the deletion and that participate in the regulation of PAH gene expression.", "contributionDate": { "date": "2021/2/11", "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": "CA281520/MONDO:0009861/006/ci/EV000001263", "traceableAuthorStatement": "https://www.ncbi.nlm.nih.gov/pubmed/11935335", "type": "CuratorInference" } ], "id": "CG-PCER-VARINT:CA281520/MONDO:0009861/006/0/1696/1698", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA281520/MONDO:0009861/006/1/1697", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA281520/MONDO:0009861/006/0/1696", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA281520/MONDO:0009861/006/el/0/1798", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA281520/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": "2021/2/11", "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/CA281520/MONDO:0009861/006/el/0/1798/1800", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA281520/MONDO:0009861/006/ci/CA281520/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": "absent from gnomAD (genome coverage > 31,000)", "contributionDate": { "date": "2021/2/11", "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": "CA281520/MONDO:0009861/006/ci/CA281520/MONDO:0009861/006.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA281520/MONDO:0009861/006/0/1798/1800", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA281520/MONDO:0009861/006/1/1799", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA281520/MONDO:0009861/006/0/1798", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA281520/MONDO:0009861/006/el/0/1633", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA281520/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": "2021/2/11", "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/CA281520/MONDO:0009861/006/el/0/1633/1635", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA281520/MONDO:0009861/006/ci/EV000001263", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50015_EP155190578201949", "id": "CG-PCER-AGENT:CG_50015_EP155190578201949", "type": "Agent" }, "comments": "We identified a patient with nonPKU HPA in family W. Classification of PAH deficiency was assigned on the basis of pretreatment phenylalanine levels in blood (Guldberg et al. 1998). A novel 5.1-kb band appeared in the DNA of the proband (Fig.2A, lane P) and his mother (lane M), in addition to the expected\n8.8-kb fragment of the normal control (lane N) and the proband′s father (lane F). This result suggested the presence of a 3.7-kb deletion in the maternal allele. DNA sequence analysis of phagemid showed that the 5.1-kb mutant fragment carried a 3767-bp deletion of the sequence nt 4020–nt 254 upstream of the RNA initiation\nsite of the PAH gene (Fig. 2B). This sequence corresponded to nt 4173–nt 407 upstream of the PAH initiation codon. The mutation was designated as –4173_-407del to conform with the nomenclature system for human gene\nmutations (Antonarakis et al. 1998).", "contributionDate": { "date": "2021/2/11", "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": "CA281520/MONDO:0009861/006/ci/EV000001263", "traceableAuthorStatement": "https://www.ncbi.nlm.nih.gov/pubmed/11935335", "type": "CuratorInference" }, { "@id": "CG-PCER:curatorInference/CA281520/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": "-4173_-407del detected on 5 chromosomes. BH4 deficiency has been ruled out in these patients.", "contributionDate": { "date": "2021/2/11", "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": "CA281520/MONDO:0009861/006/ci/EV000000028", "traceableAuthorStatement": "https://www.ncbi.nlm.nih.gov/pubmed/24401910", "type": "CuratorInference" } ], "id": "CG-PCER-VARINT:CA281520/MONDO:0009861/006/0/1633/1635", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA281520/MONDO:0009861/006/1/1634", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA281520/MONDO:0009861/006/0/1633", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA281520/MONDO:0009861/006/el/0/1651", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA281520/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": "2021/2/11", "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/0058", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000330", "id": "SEPIO:0000330", "label": "Pathogenic Strong" }, "id": "0058", "label": "PM3", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA281520/MONDO:0009861/006/el/0/1651/1653", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA281520/MONDO:0009861/006/ci/EV000001263", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50015_EP155190578201949", "id": "CG-PCER-AGENT:CG_50015_EP155190578201949", "type": "Agent" }, "comments": "The parenthood of the proband was confirmed by DNA fingerprinting. By linkage analysis to the c.1155G/C (L385L) polymorphic marker, the c.227A→G substitution was deduced to be inherited from the father. Thus, the E76G mutation was most likely a de novo mutation that had occurred during spermatogenesis. In addition to proband BF of family W, probands of two other families, X and AU, were also found to carry this deletion and were both compound heterozygote\nwith the other allele carrying the R408Q mutation.", "contributionDate": { "date": "2021/2/11", "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": "CA281520/MONDO:0009861/006/ci/EV000001263", "traceableAuthorStatement": "https://www.ncbi.nlm.nih.gov/pubmed/11935335", "type": "CuratorInference" }, { "@id": "CG-PCER:curatorInference/CA281520/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": "5: −4173_−407del+E286K (2 patients). 11:−4173_−407del+E76G (likely same patient as Chen 2002). 14:−4173_−407del+R408Q (2 patients, likely same patients as Chen 2002).", "contributionDate": { "date": "2021/2/11", "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": "CA281520/MONDO:0009861/006/ci/EV000000028", "traceableAuthorStatement": "https://www.ncbi.nlm.nih.gov/pubmed/24401910", "type": "CuratorInference" } ], "id": "CG-PCER-VARINT:CA281520/MONDO:0009861/006/0/1651/1653", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA281520/MONDO:0009861/006/1/1652", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA281520/MONDO:0009861/006/0/1651", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA281520/MONDO:0009861/006", "metadata": { "created": "2024-09-27T21:34:50.839Z", "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 21:34:50 -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": "00b68297-2f63-4952-bc0d-108c6dfecefb", "variant": { "@id": "https://reg.genome.network/allele/CA281520", "id": "CAR:CA281520", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000277.1:c.-4165_-407del" } ], "preferred": true }, { "alleleName": [ { "name": "NM_000277.1:c.-4165_-407del3759" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000277.1(PAH):c.-4165_-407del3759" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-11-02T00:16:46.704Z" } }, "status": { "code": 200, "name": "OK" } }