{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/da5189c2-5507-488f-b202-b7e8bd60fb5e/doc/sepio/version/2.0.0", "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 1.2.0", "type": "VariantPathogenicityInterpretationGuideline", "version": "1.2.0" }, "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/CA356987/MONDO:0001586/091/el/0/1696", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA356987/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": "2026/5/14", "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/CA356987/MONDO:0001586/091/el/0/1696/1698", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA356987/MONDO:0001586/091/ci/EV000001747", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50009_EP157972030954718", "id": "CG-PCER-AGENT:CG_50009_EP157972030954718", "type": "Agent" }, "comments": "Expression of the variant in COS-7 cells resulted in less than 0.4% wild type IDUA activity indicating that this variant may impact protein function (PMID:12189649)(PS3_Supporting)", "contributionDate": { "date": "2026/5/14", "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": "CA356987/MONDO:0001586/091/ci/EV000001747", "traceableAuthorStatement": "https://www.ncbi.nlm.nih.gov/pubmed/12189649", "type": "CuratorInference" } ], "id": "CG-PCER-VARINT:CA356987/MONDO:0001586/091/0/1696/1698", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA356987/MONDO:0001586/091/1/1697", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA356987/MONDO:0001586/091/0/1696", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA356987/MONDO:0001586/091/el/0/1615", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA356987/MONDO:0001586/091/ei/1/1616", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50009_EP157972030954718", "id": "CG-PCER-AGENT:CG_50009_EP157972030954718", "type": "Agent" }, "contributionDate": { "date": "2026/5/14", "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/CA356987/MONDO:0001586/091/el/0/1615/1617", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA356987/MONDO:0001586/091/ci/CA356987/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" }, "contributionDate": { "date": "2026/5/14", "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": "CA356987/MONDO:0001586/091/ci/CA356987/MONDO:0001586/091.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA356987/MONDO:0001586/091/0/1615/1617", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA356987/MONDO:0001586/091/1/1616", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA356987/MONDO:0001586/091/0/1615", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA356987/MONDO:0001586/091/el/0/1780", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA356987/MONDO:0001586/091/ei/1/1781", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50009_EP157972030954718", "id": "CG-PCER-AGENT:CG_50009_EP157972030954718", "type": "Agent" }, "contributionDate": { "date": "2026/5/14", "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/CA356987/MONDO:0001586/091/el/0/1780/1782", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA356987/MONDO:0001586/091/ci/CA356987/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": "Another missense variant, c.235G>A (p.Ala79Thr), in the same codon has been classified as benign.", "contributionDate": { "date": "2026/5/14", "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": "CA356987/MONDO:0001586/091/ci/CA356987/MONDO:0001586/091.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA356987/MONDO:0001586/091/0/1780/1782", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA356987/MONDO:0001586/091/1/1781", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA356987/MONDO:0001586/091/0/1780", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA356987/MONDO:0001586/091/el/0/1831", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA356987/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": "2026/5/14", "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/CA356987/MONDO:0001586/091/el/0/1831/1833", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA356987/MONDO:0001586/091/ci/CA356987/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\nrange in leukocytes, urinary GAGs elevation above normal range, and clinical features specific to MPS I including hepatosplenomegaly, and corneal involvement (PMID: 27520059; PP4_Moderate).", "contributionDate": { "date": "2026/5/14", "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": "CA356987/MONDO:0001586/091/ci/CA356987/MONDO:0001586/091.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA356987/MONDO:0001586/091/0/1831/1833", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA356987/MONDO:0001586/091/1/1832", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA356987/MONDO:0001586/091/0/1831", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA356987/MONDO:0001586/091/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA356987/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": "2026/5/14", "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/CA356987/MONDO:0001586/091/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA356987/MONDO:0001586/091/ci/CA356987/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 0.738 which is in the range 0.644-\n0.773, evidence that correlates with impact to IDUA function at the supporting level (Pejaver et al.) (PP3).", "contributionDate": { "date": "2026/5/14", "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": "CA356987/MONDO:0001586/091/ci/CA356987/MONDO:0001586/091.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA356987/MONDO:0001586/091/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA356987/MONDO:0001586/091/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA356987/MONDO:0001586/091/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA356987/MONDO:0001586/091/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA356987/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": "2026/5/14", "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/CA356987/MONDO:0001586/091/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA356987/MONDO:0001586/091/ci/CA356987/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 is absent in gnomAD v4.1.0 (PM2_Supporting).\n(Note that a variant with the same protein change occurs on a different IDUA transcript is listed in gnomAD v4.1.0.)", "contributionDate": { "date": "2026/5/14", "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": "CA356987/MONDO:0001586/091/ci/CA356987/MONDO:0001586/091.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA356987/MONDO:0001586/091/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA356987/MONDO:0001586/091/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA356987/MONDO:0001586/091/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA356987/MONDO:0001586/091/el/0/1669", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA356987/MONDO:0001586/091/ei/1/1670", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50009_EP157972030954718", "id": "CG-PCER-AGENT:CG_50009_EP157972030954718", "type": "Agent" }, "contributionDate": { "date": "2026/5/14", "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/CA356987/MONDO:0001586/091/el/0/1669/1671", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA356987/MONDO:0001586/091/ci/CA356987/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 11 individuals with MPS I. Of those individuals, 3 were compound heterozygous, phase confirmed in trans by parental testing, for the variant and a variant in IDUA that has been classified as likely pathogenic or pathogenic by the ClinGen LD VCEP (variants: c.1037T>G (p.Leu346Arg, ClinVar Variation ID: 11927), c.1877G>A (p.Trp626Ter, ClinVar Variation ID: 928997) and c.1402+1G>T (ClinVar Variation ID: 1323099) (3 x 1.0 points = 3.0 points). Another five individuals are compound heterozygous for the variant and a variant in IDUA, either c.536C>G (p.Thr179Arg) (ClinVar Variation ID: 556358), c.589G>A (p.Val197Ile) (ClinVar Variation ID: 2720835), c.265C>T (p.Arg89Trp) (ClinVar Variation ID: 580286), or c.1037T>G (p.Leu346Arg) (ClinVar Variation ID: 11927) (PMIDs: 27520059, 21480867). The allelic data from these individuals will be used in the assessment of the second variant. Three individuals were homozygous for the variant (1 point; PMID: 21480867). Total 4.0 points (PM3_VeryStrong). ", "contributionDate": { "date": "2026/5/14", "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": "CA356987/MONDO:0001586/091/ci/CA356987/MONDO:0001586/091.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA356987/MONDO:0001586/091/0/1669/1671", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA356987/MONDO:0001586/091/1/1670", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA356987/MONDO:0001586/091/0/1669", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA356987/MONDO:0001586/091", "metadata": { "created": "2026-05-14T12:53:11.446Z", "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": "Thu, 14 May 2026 12:53:11 -0000", "schemaLabel": "Evidence Repository.Beta-1 (Unofficial)", "version": "2.0.0" }, "statementOutcome": { "@id": "https://loinc.org/LA6668-3", "id": "LN:LA6668-3", "label": "Pathogenic" }, "type": "VariantPathogenicityInterpretation", "uuid": "da5189c2-5507-488f-b202-b7e8bd60fb5e", "variant": { "@id": "https://reg.genome.network/allele/CA356987", "id": "CAR:CA356987", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000203.5:c.236C>T" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000203.5(IDUA):c.236C>T (p.Ala79Val)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-11-01T13:44:39.305Z" } }, "status": { "code": 200, "name": "OK" } }