{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/7e224408-fb91-49f8-9218-48e07c8d2739/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/CA355961899/MONDO:0001586/091/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA355961899/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": "2025/7/17", "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/CA355961899/MONDO:0001586/091/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA355961899/MONDO:0001586/091/ci/CA355961899/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 0.000000848 (1/1,179,052 alleles) in the European (non-Finnish) population; this is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025) meeting this criterion (PM2_Supporting). ", "contributionDate": { "date": "2025/7/17", "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": "CA355961899/MONDO:0001586/091/ci/CA355961899/MONDO:0001586/091.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA355961899/MONDO:0001586/091/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA355961899/MONDO:0001586/091/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA355961899/MONDO:0001586/091/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA355961899/MONDO:0001586/091/el/0/1717", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA355961899/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": "2025/7/17", "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/CA355961899/MONDO:0001586/091/el/0/1717/1719", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA355961899/MONDO:0001586/091/ci/CA355961899/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 detected in at least four probands with MPS1. Of these individuals, one was 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.46_57del (ClinVar Variation ID: 92643) (PMID: 21394825, 33072983, 1 patient 1 x 0.5 points due to phase unknown). Two individuals were homozygous for the variant (max 2 x 0.5). PM3_Moderate, total 1.5 points. Another patient was compound heterozygous for the variant and c.-14_10del (PMID: 21394825). The allelic data from this patient will be used in the classification of c.-14_10del and is not included here to avoid circular logic.", "contributionDate": { "date": "2025/7/17", "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": "CA355961899/MONDO:0001586/091/ci/CA355961899/MONDO:0001586/091.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA355961899/MONDO:0001586/091/0/1717/1719", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA355961899/MONDO:0001586/091/1/1718", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA355961899/MONDO:0001586/091/0/1717", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA355961899/MONDO:0001586/091/el/0/1594", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA355961899/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": "2025/7/17", "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/CA355961899/MONDO:0001586/091/el/0/1594/1596", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA355961899/MONDO:0001586/091/ci/CA355961899/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.603C>G (p.Tyr201Ter) is a nonsense variant predicted to cause a premature stop codon in exon 6 out of a total of 14 exons, leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).", "contributionDate": { "date": "2025/7/17", "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": "CA355961899/MONDO:0001586/091/ci/CA355961899/MONDO:0001586/091.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA355961899/MONDO:0001586/091/0/1594/1596", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA355961899/MONDO:0001586/091/1/1595", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA355961899/MONDO:0001586/091/0/1594", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA355961899/MONDO:0001586/091/el/0/1831", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA355961899/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": "2025/7/17", "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/CA355961899/MONDO:0001586/091/el/0/1831/1833", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA355961899/MONDO:0001586/091/ci/CA355961899/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": "MPS I was confirmed in one newborn female with very low enzyme activity in leucocytes of 1.6% and high excretion of heparan sulfate (HS) at 220.6 (nv < 4.6) and dermatan sulfate (DS) at 90.6 (nv < 38.1) in urine, had clinical features of a severe Hurler phenotype (PMID: 33072983). More studies report the same case (PMID: 33147872, PMID: 32432561), a female of Italian origin is now 2.5 years old. On initial examination at 15 days of life, she had clinical features of a severe form of the disease: corneal clouding, coarse facial features, moderate sensorineural hearing loss, poor growth, rounding of the iliac wings, and large cisterna magna at brain MRI. This phenotype was confirmed by elevated urinary GAGs (HS 121.9 mg/mMol creatinine, nv < 4.6; DS 80.0 mg/mMol creatinine, nv < 38.1) (PP4_Moderate).", "contributionDate": { "date": "2025/7/17", "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": "CA355961899/MONDO:0001586/091/ci/CA355961899/MONDO:0001586/091.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA355961899/MONDO:0001586/091/0/1831/1833", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA355961899/MONDO:0001586/091/1/1832", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA355961899/MONDO:0001586/091/0/1831", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA355961899/MONDO:0001586/091", "metadata": { "created": "2025-07-17T15:24:03.251Z", "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, 17 Jul 2025 15:24:03 -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": "7e224408-fb91-49f8-9218-48e07c8d2739", "variant": { "@id": "https://reg.genome.network/allele/CA355961899", "id": "CAR:CA355961899", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000203.5:c.603C>G" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000203.5(IDUA):c.603C>G (p.Tyr201Ter)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-11-04T21:43:02.485Z" } }, "status": { "code": 200, "name": "OK" } }