{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/fa1dcac4-03bb-478f-abc1-32be14c13626/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/CA91167598/MONDO:0001586/091/el/0/1762", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA91167598/MONDO:0001586/091/ei/1/1763", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50009_EP157972030954718", "id": "CG-PCER-AGENT:CG_50009_EP157972030954718", "type": "Agent" }, "contributionDate": { "date": "2025/12/28", "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/CA91167598/MONDO:0001586/091/el/0/1762/1764", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA91167598/MONDO:0001586/091/ci/CA91167598/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 c.590G>A variant in IDUA alters the first nucleotide of exon 6. A minigene assay revealed that the variant results in a major transcript with complete retention of intron 5, as well as several alternative transcripts with retention of the last 22, 25 and 28 nucleotides of intron 5. Complete retention of intron 5 leads to a premature stop codon, p.Phe198ValfsTer127 (PMID: 39754079) (PVS1_Strong). Note that the SpliceAI score for acceptor loss for c.590G>A is 0.19 (just below the required threshold of >0.2 for prediction of splice impact). PVS1_Very strong was not used because the mini gene assay results were missing from the publication. ", "contributionDate": { "date": "2025/12/28", "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": "CA91167598/MONDO:0001586/091/ci/CA91167598/MONDO:0001586/091.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA91167598/MONDO:0001586/091/0/1762/1764", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA91167598/MONDO:0001586/091/1/1763", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA91167598/MONDO:0001586/091/0/1762", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA91167598/MONDO:0001586/091/el/0/1633", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA91167598/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": "2025/12/28", "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/CA91167598/MONDO:0001586/091/el/0/1633/1635", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA91167598/MONDO:0001586/091/ci/CA91167598/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 variant has been reported in at least two probands with MPS 1(PMID: 32188113, 12203999, 39754079). One has an attenuated phenotype and is part of a cohort in which the diagnosis was “based on the clinical features, excessive urinary glycosaminoglycan excretion, and reduced IDUA activity in fibroblasts and/or leukocytes (PMID: 12203999). The second is a fetus terminated at 35GW, which showed signs of MPS 1. Ultrasound examination at 24.0 GW revealed hepatosplenomegaly and dysmorphic features, including a long, broad philtrum, as well as echogenic spots in the liver, spleen, peritoneum, and thymus. IDUA activity in cultured amniocytes was deficient (0.3 µkat/kg normal 33.8 µkat/kg). Placenta analysis showed a single umbilical artery and a microvacuolized appearance of Hofbauer cells, compatible with lysosomal overload (PMID: 39754079) (PP4_Supporting). Of note, another variant, c.494-57G>A, was found to be in cis with c.590G>A in the affected fetus. ", "contributionDate": { "date": "2025/12/28", "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": "CA91167598/MONDO:0001586/091/ci/CA91167598/MONDO:0001586/091.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA91167598/MONDO:0001586/091/0/1633/1635", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA91167598/MONDO:0001586/091/1/1634", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA91167598/MONDO:0001586/091/0/1633", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA91167598/MONDO:0001586/091/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA91167598/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": "2025/12/28", "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/CA91167598/MONDO:0001586/091/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA91167598/MONDO:0001586/091/ci/CA91167598/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 is 0.000007633 (9/1179014 alleles) in the European (non-Finnish) genetic ancestry group; this is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025) due to which we can apply PM2_Supporting.", "contributionDate": { "date": "2025/12/28", "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": "CA91167598/MONDO:0001586/091/ci/CA91167598/MONDO:0001586/091.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA91167598/MONDO:0001586/091/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA91167598/MONDO:0001586/091/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA91167598/MONDO:0001586/091/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA91167598/MONDO:0001586/091/el/0/1717", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA91167598/MONDO:0001586/091/ei/1/1718", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50009_EP157972030954718", "id": "CG-PCER-AGENT:CG_50009_EP157972030954718", "type": "Agent" }, "contributionDate": { "date": "2025/12/28", "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/CA91167598/MONDO:0001586/091/el/0/1717/1719", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA91167598/MONDO:0001586/091/ci/CA91167598/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 variant has been reported in at least two probands with MPS 1(PMID: 32188113, 12203999, 39754079). Both of these individuals are compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic for MPS I by the ClinGen LD VCEP, including c.1598C>G (p.Pro533Arg) (ClinVar Variation ID: 11910) (PMID: 32188113, 12203999: PM3, 0.5 points, phase unknown) and c.1139dup (PMID: 39754079, trans confirmed, 1 point) (total 1.5 points, PM3_Moderate)", "contributionDate": { "date": "2025/12/28", "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": "CA91167598/MONDO:0001586/091/ci/CA91167598/MONDO:0001586/091.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA91167598/MONDO:0001586/091/0/1717/1719", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA91167598/MONDO:0001586/091/1/1718", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA91167598/MONDO:0001586/091/0/1717", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA91167598/MONDO:0001586/091", "metadata": { "created": "2025-12-28T21:05:49.216Z", "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": "Sun, 28 Dec 2025 21:05:49 -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": "fa1dcac4-03bb-478f-abc1-32be14c13626", "variant": { "@id": "https://reg.genome.network/allele/CA91167598", "id": "CAR:CA91167598", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000203.5:c.590G>A" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000203.5(IDUA):c.590G>A (p.Gly197Asp)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-11-01T06:43:47.585Z" } }, "status": { "code": 200, "name": "OK" } }