{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/36f5b707-fb05-4fe2-8fc2-8494a52a3188/doc/sepio/version/1.0.0", "assertionMethod": { "@id": "https://cspec.genome.network/cspec/SequenceVariantInterpretation/id/1529725529", "label": "ClinGen Lysosomal Diseases Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for IDUA Version 1.0.0", "type": "VariantPathogenicityInterpretationGuideline", "version": "1.0.0" }, "condition": { "@id": "https://api.monarchinitiative.org/api/bioentity/phenotype/MONDO:0001586", "id": "MONDO:0001586", "label": "mucopolysaccharidosis type 1", "type": "GeneticCondition" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA2802126/MONDO:0001586/091/el/0/1633", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA2802126/MONDO:0001586/091/ei/1/1634", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50009_EP157972030954718", "id": "CG-PCER-AGENT:CG_50009_EP157972030954718", "type": "Agent" }, "contributionDate": { "date": "2025/9/16", "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/CA2802126/MONDO:0001586/091/el/0/1633/1635", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA2802126/MONDO:0001586/091/ci/CA2802126/MONDO:0001586/091.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50009_EP157972030954718", "id": "CG-PCER-AGENT:CG_50009_EP157972030954718", "type": "Agent" }, "comments": "One patient from Pakistan, homozygous for the variant, was diagnosed with attenuated MPS I (described as having Scheie syndrome) and low IDUA activity (PMID: 11735025) (PP4) ", "contributionDate": { "date": "2025/9/16", "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": "CA2802126/MONDO:0001586/091/ci/CA2802126/MONDO:0001586/091.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA2802126/MONDO:0001586/091/0/1633/1635", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA2802126/MONDO:0001586/091/1/1634", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA2802126/MONDO:0001586/091/0/1633", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA2802126/MONDO:0001586/091/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA2802126/MONDO:0001586/091/ei/1/1637", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50009_EP157972030954718", "id": "CG-PCER-AGENT:CG_50009_EP157972030954718", "type": "Agent" }, "contributionDate": { "date": "2025/9/16", "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/CA2802126/MONDO:0001586/091/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA2802126/MONDO:0001586/091/ci/CA2802126/MONDO:0001586/091.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50009_EP157972030954718", "id": "CG-PCER-AGENT:CG_50009_EP157972030954718", "type": "Agent" }, "comments": "The highest population minor allele frequency in gnomAD v4.1.0 is 0.0001673 (1/5976 alleles) in the Middle Eastern population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting).", "contributionDate": { "date": "2025/9/16", "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": "CA2802126/MONDO:0001586/091/ci/CA2802126/MONDO:0001586/091.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA2802126/MONDO:0001586/091/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA2802126/MONDO:0001586/091/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA2802126/MONDO:0001586/091/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA2802126/MONDO:0001586/091/el/0/1690", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA2802126/MONDO:0001586/091/ei/1/1691", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50009_EP157972030954718", "id": "CG-PCER-AGENT:CG_50009_EP157972030954718", "type": "Agent" }, "contributionDate": { "date": "2025/9/16", "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/CA2802126/MONDO:0001586/091/el/0/1690/1692", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA2802126/MONDO:0001586/091/ci/CA2802126/MONDO:0001586/091.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50009_EP157972030954718", "id": "CG-PCER-AGENT:CG_50009_EP157972030954718", "type": "Agent" }, "comments": "The computational predictor REVEL gives a score of 0.896 which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level based on the specifications of the ClinGen Lysosomal Diseases VCEP (PMID: 36413997) (PP3_Moderate). SpliceAI predicts that the variant has no impact on splicing.", "contributionDate": { "date": "2025/9/16", "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": "CA2802126/MONDO:0001586/091/ci/CA2802126/MONDO:0001586/091.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA2802126/MONDO:0001586/091/0/1690/1692", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA2802126/MONDO:0001586/091/1/1691", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA2802126/MONDO:0001586/091/0/1690", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA2802126/MONDO:0001586/091/el/0/1609", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA2802126/MONDO:0001586/091/ei/1/1610", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50009_EP157972030954718", "id": "CG-PCER-AGENT:CG_50009_EP157972030954718", "type": "Agent" }, "contributionDate": { "date": "2025/9/16", "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/CA2802126/MONDO:0001586/091/el/0/1609/1611", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA2802126/MONDO:0001586/091/ci/CA2802126/MONDO:0001586/091.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50009_EP157972030954718", "id": "CG-PCER-AGENT:CG_50009_EP157972030954718", "type": "Agent" }, "comments": "This variant has been detected in at least 01 individuals with MPS I. This individual was homozygous for the variant (0.5 points, PMID: 11735025) (PM3_supporting).", "contributionDate": { "date": "2025/9/16", "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": "CA2802126/MONDO:0001586/091/ci/CA2802126/MONDO:0001586/091.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA2802126/MONDO:0001586/091/0/1609/1611", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA2802126/MONDO:0001586/091/1/1610", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA2802126/MONDO:0001586/091/0/1609", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA2802126/MONDO:0001586/091/el/0/1696", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA2802126/MONDO:0001586/091/ei/1/1697", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50009_EP157972030954718", "id": "CG-PCER-AGENT:CG_50009_EP157972030954718", "type": "Agent" }, "contributionDate": { "date": "2025/9/16", "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/CA2802126/MONDO:0001586/091/el/0/1696/1698", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA2802126/MONDO:0001586/091/ci/EV000001752", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50009_EP157972030954718", "id": "CG-PCER-AGENT:CG_50009_EP157972030954718", "type": "Agent" }, "comments": "Table 8. When expressed in COS cells the IDUA activity of the variant is 5.2 nmol/h/mg cell protein. This is equal to the IDUA activity in COS cells alone (5.2 nmol/h/mg cell protein). The negative control (empty vector) has activity of 4.2 nmol/h/mg cell protein. Activity of WT IDUA expressed in COS cells is 88.1 nmol/h/mg cell protein. \nAlthough the cDNA change for this variant was not explicitly stated, it was confirmed from the primer sequences used for site-directed mutagenesis (see Table 4)", "contributionDate": { "date": "2025/9/16", "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": "CA2802126/MONDO:0001586/091/ci/EV000001752", "traceableAuthorStatement": "https://www.ncbi.nlm.nih.gov/pubmed/11735025", "type": "CuratorInference" } ], "id": "CG-PCER-VARINT:CA2802126/MONDO:0001586/091/0/1696/1698", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA2802126/MONDO:0001586/091/1/1697", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA2802126/MONDO:0001586/091/0/1696", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA2802126/MONDO:0001586/091", "metadata": { "created": "2025-09-16T15:04:47.929Z", "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": "Tue, 16 Sep 2025 15:04:47 -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": "36f5b707-fb05-4fe2-8fc2-8494a52a3188", "variant": { "@id": "https://reg.genome.network/allele/CA2802126", "id": "CAR:CA2802126", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000203.5:c.956C>T" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000203.5(IDUA):c.956C>T (p.Ala319Val)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-11-04T20:31:47.891Z" } }, "status": { "code": 200, "name": "OK" } }