{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/827b53ba-aaa5-414e-93ca-377fab47a169/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/CA355962511/MONDO:0001586/091/el/0/1633", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA355962511/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": "2025/7/18", "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/CA355962511/MONDO:0001586/091/el/0/1633/1635", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA355962511/MONDO:0001586/091/ci/CA355962511/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": "At least 2 patients with this variant had documented IDUA deficiency within the affected range in leukocytes and clinical features specific to MPS I including dysostosis multiplex, hepatosplenomegaly, arthropathy, and corneal involvement (PMIDs: 16438163, 27146977) (PP4).", "contributionDate": { "date": "2025/7/18", "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": "CA355962511/MONDO:0001586/091/ci/CA355962511/MONDO:0001586/091.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA355962511/MONDO:0001586/091/0/1633/1635", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA355962511/MONDO:0001586/091/1/1634", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA355962511/MONDO:0001586/091/0/1633", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA355962511/MONDO:0001586/091/el/0/1717", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA355962511/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": "2025/7/18", "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/CA355962511/MONDO:0001586/091/el/0/1717/1719", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA355962511/MONDO:0001586/091/ci/CA355962511/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 2 individuals with MPS I. Of those individuals, 1\nwas compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic for MPS I by the ClinGen LD VCEP, c.223G>A (p.Ala75Thr) (ClinVar Variation ID: 222993); the phase was not confirmed (0.5 points; PMID: 27146977). One individual was homozygous for the variant (ClinVar SCV002562742.2) (0.5 points). Total 1 point (PM3). Another patient was compound heterozygous for the variant and c.164dup (PMID: 16438163). The allelic data for this patient will be used to support the classification of c.164dup and is not included here in order to avoid circular logic.", "contributionDate": { "date": "2025/7/18", "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": "CA355962511/MONDO:0001586/091/ci/CA355962511/MONDO:0001586/091.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA355962511/MONDO:0001586/091/0/1717/1719", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA355962511/MONDO:0001586/091/1/1718", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA355962511/MONDO:0001586/091/0/1717", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA355962511/MONDO:0001586/091/el/0/1594", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA355962511/MONDO:0001586/091/ei/1/1595", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50009_EP157972030954718", "id": "CG-PCER-AGENT:CG_50009_EP157972030954718", "type": "Agent" }, "contributionDate": { "date": "2025/7/18", "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/CA355962511/MONDO:0001586/091/el/0/1594/1596", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA355962511/MONDO:0001586/091/ci/CA355962511/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 NM_000203.5(IDUA):c.895G>T (p.Glu299Ter) variant in IDUA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant exon 7 out of 14, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).", "contributionDate": { "date": "2025/7/18", "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": "CA355962511/MONDO:0001586/091/ci/CA355962511/MONDO:0001586/091.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA355962511/MONDO:0001586/091/0/1594/1596", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA355962511/MONDO:0001586/091/1/1595", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA355962511/MONDO:0001586/091/0/1594", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA355962511/MONDO:0001586/091/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA355962511/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": "2025/7/18", "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/CA355962511/MONDO:0001586/091/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA355962511/MONDO:0001586/091/ci/CA355962511/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 0.000023 (2/86636 alleles) in the South Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting).", "contributionDate": { "date": "2025/7/18", "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": "CA355962511/MONDO:0001586/091/ci/CA355962511/MONDO:0001586/091.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA355962511/MONDO:0001586/091/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA355962511/MONDO:0001586/091/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA355962511/MONDO:0001586/091/0/1636", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA355962511/MONDO:0001586/091", "metadata": { "created": "2025-07-18T20:02:59.365Z", "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, 18 Jul 2025 20:02:59 -0000", "schemaLabel": "Evidence Repository.Beta-1 (Unofficial)", "version": "1.0.0" }, "statementOutcome": { "@id": "https://loinc.org/LA6668-3", "id": "LN:LA6668-3", "label": "Pathogenic" }, "type": "VariantPathogenicityInterpretation", "uuid": "827b53ba-aaa5-414e-93ca-377fab47a169", "variant": { "@id": "https://reg.genome.network/allele/CA355962511", "id": "CAR:CA355962511", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000203.5:c.895G>T" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000203.5(IDUA):c.895G>T (p.Glu299Ter)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-10-29T00:08:20.860Z" } }, "status": { "code": 200, "name": "OK" } }