{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/5b06d215-7444-4f08-bce3-9eedaff7c66d/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 1.1.0", "type": "VariantPathogenicityInterpretationGuideline", "version": "1.1.0" }, "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/CA2802464/MONDO:0001586/091/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA2802464/MONDO:0001586/091/ei/1/1748", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50009_EP157972030954718", "id": "CG-PCER-AGENT:CG_50009_EP157972030954718", "type": "Agent" }, "contributionDate": { "date": "2025/12/29", "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/CA2802464/MONDO:0001586/091/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA2802464/MONDO:0001586/091/ci/CA2802464/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 0.667 which is in the range 0.644-0.773, evidence that correlates with impact to IDUA function at the supporting level (PMID: 36413997) (PP3).", "contributionDate": { "date": "2025/12/29", "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": "CA2802464/MONDO:0001586/091/ci/CA2802464/MONDO:0001586/091.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA2802464/MONDO:0001586/091/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA2802464/MONDO:0001586/091/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA2802464/MONDO:0001586/091/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA2802464/MONDO:0001586/091/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA2802464/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": "2025/12/29", "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/CA2802464/MONDO:0001586/091/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA2802464/MONDO:0001586/091/ci/CA2802464/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 0.00001336 (1/74840 alleles) in the African/African American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting).\n", "contributionDate": { "date": "2025/12/29", "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": "CA2802464/MONDO:0001586/091/ci/CA2802464/MONDO:0001586/091.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA2802464/MONDO:0001586/091/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA2802464/MONDO:0001586/091/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA2802464/MONDO:0001586/091/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA2802464/MONDO:0001586/091/el/0/1825", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA2802464/MONDO:0001586/091/ei/1/1826", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50009_EP157972030954718", "id": "CG-PCER-AGENT:CG_50009_EP157972030954718", "type": "Agent" }, "contributionDate": { "date": "2025/12/29", "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/CA2802464/MONDO:0001586/091/el/0/1825/1827", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA2802464/MONDO:0001586/091/ci/CA2802464/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": "When expressed in CHO cells, the variant had <1% activity in cell lysate compared to WT (Table 4) and significantly reduced amount of protein with reduced processing on Western blot (Fig. 1) (PMID: 12559846)", "contributionDate": { "date": "2025/12/29", "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": "CA2802464/MONDO:0001586/091/ci/CA2802464/MONDO:0001586/091.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA2802464/MONDO:0001586/091/0/1825/1827", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA2802464/MONDO:0001586/091/1/1826", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA2802464/MONDO:0001586/091/0/1825", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA2802464/MONDO:0001586/091/el/0/1609", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA2802464/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": "2025/12/29", "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/CA2802464/MONDO:0001586/091/el/0/1609/1611", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA2802464/MONDO:0001586/091/ci/CA2802464/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 is compound heterozygous for the variant and another variant in IDUA that has been classified by the ClinGen LD VCEP as pathogenic for MPS I, c.1139A>G (p.Gln380Arg). The phase is unknown ( PMID: 12559846, 18792977). Another patient is compound heterozygous for the variant and c.979G>C (p.Ala327Pro). The allelic data from the second patient will be used in the classification of p.Ala327Pro and is not included here to avoid circular logic. Total points = 0.5 (PM3_Supporting)", "contributionDate": { "date": "2025/12/29", "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": "CA2802464/MONDO:0001586/091/ci/CA2802464/MONDO:0001586/091.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA2802464/MONDO:0001586/091/0/1609/1611", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA2802464/MONDO:0001586/091/1/1610", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA2802464/MONDO:0001586/091/0/1609", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA2802464/MONDO:0001586/091/el/0/1831", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA2802464/MONDO:0001586/091/ei/1/1832", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50009_EP157972030954718", "id": "CG-PCER-AGENT:CG_50009_EP157972030954718", "type": "Agent" }, "contributionDate": { "date": "2025/12/29", "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/CA2802464/MONDO:0001586/091/el/0/1831/1833", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA2802464/MONDO:0001586/091/ci/CA2802464/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": "Two patients with a diagnosis of MPS I, both of German origin, have been reported with the variant. A detailed report was available for one of these patients who had attenuated disease with documented low levels of IDUA activity in plasma and leukocytes, clinical symptoms consistent with MPS I, and elevated CSF GAG levels which decreased into the normal range after intrathecal ERT (PMID: 18792977) (PP4_Moderate).", "contributionDate": { "date": "2025/12/29", "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": "CA2802464/MONDO:0001586/091/ci/CA2802464/MONDO:0001586/091.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA2802464/MONDO:0001586/091/0/1831/1833", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA2802464/MONDO:0001586/091/1/1832", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA2802464/MONDO:0001586/091/0/1831", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA2802464/MONDO:0001586/091", "metadata": { "created": "2025-12-29T16:19:07.491Z", "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": "Mon, 29 Dec 2025 16:19:07 -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": "5b06d215-7444-4f08-bce3-9eedaff7c66d", "variant": { "@id": "https://reg.genome.network/allele/CA2802464", "id": "CAR:CA2802464", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000203.5:c.1883G>C" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000203.5(IDUA):c.1883G>C (p.Arg628Pro)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-10-14T17:14:55.859Z" } }, "status": { "code": 200, "name": "OK" } }