{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/29bc99e3-6288-43e4-9650-419a4e857e56/doc/sepio/version/1.0.0", "assertionMethod": { "@id": "https://cspec.genome.network/cspec/SequenceVariantInterpretation/id/1745680620", "label": "ClinGen Hemoglobinopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HBA2 Version 1.0.0", "type": "VariantPathogenicityInterpretationGuideline", "version": "1.0.0" }, "condition": { "@id": "https://api.monarchinitiative.org/api/bioentity/phenotype/MONDO:0100562", "id": "MONDO:0100562", "label": "HBA2-related alpha thalassemia spectrum", "type": "GeneticCondition" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA125593/MONDO:0100562/173/el/0/1699", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA125593/MONDO:0100562/173/ei/1/1700", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50052_EP177555712278789", "id": "CG-PCER-AGENT:CG_50052_EP177555712278789", "type": "Agent" }, "contributionDate": { "date": "2026/4/8", "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/CA125593/MONDO:0100562/173/el/0/1699/1701", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA125593/MONDO:0100562/173/ci/CA125593/MONDO:0100562/173.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50052_EP177555712278789", "id": "CG-PCER-AGENT:CG_50052_EP177555712278789", "type": "Agent" }, "comments": "This variant has been reported in ten unrelated individuals meeting reduced MCV, MCH [7*0.15=1.05] or reduced MCV, MCH and normal RBC count [3*0.2=0.6]. Total score is 1.65 [PMID: 29219637; 23094635; 8136277; 9629496]", "contributionDate": { "date": "2026/4/8", "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": "CA125593/MONDO:0100562/173/ci/CA125593/MONDO:0100562/173.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA125593/MONDO:0100562/173/0/1699/1701", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA125593/MONDO:0100562/173/1/1700", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA125593/MONDO:0100562/173/0/1699", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA125593/MONDO:0100562/173/el/0/1648", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA125593/MONDO:0100562/173/ei/1/1649", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50052_EP177555712278789", "id": "CG-PCER-AGENT:CG_50052_EP177555712278789", "type": "Agent" }, "contributionDate": { "date": "2026/4/8", "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/CA125593/MONDO:0100562/173/el/0/1648/1650", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA125593/MONDO:0100562/173/ci/CA125593/MONDO:0100562/173.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50052_EP177555712278789", "id": "CG-PCER-AGENT:CG_50052_EP177555712278789", "type": "Agent" }, "comments": "The variant has been reported to segregate with disease in 8 affected family members from 8 families. The total number of unaffected segregations is 4. The LOD score is 5.32.\n\nPMID: 29219637: 2 families with homozygous probands with HbH disease, parents all tested and heterozygous carriers. LOD: 1.2\nPMID: 23094635: family B: both parents heterozygous carriers, proband homozygous and 2 siblings are heterozygous carriers and one sibling without the variant. LOD: 0.98\nfamily C: Homozygous proband, family pedigree structure is unclear. LOD: 0.6\nPMID: 8136277: 3\nFamily A: proband with HbH disease comp het: Hb Agrinio-Hb TSaudi, Both parents tested, mother is carrier of Hb Agrinio. LOD: 0.6\nFamily D: proband with HbH disease comp het: Hb Agrinio-Hb TSaudi, Both parents tested, mother is carrier of Hb Agrinio. One sibling who has 2 normal alleles. LOD: 0.73\nFamily F: proband with HbH disease comp het: Hb Agrinio-Hb TSaudi, Both parents tested, mother is carrier of Hb Agrinio. LOD: 0.6\nPMID: 9629496: 1 homozygous proband with HbH disease, parents tested. LOD: 0.6\n\n", "contributionDate": { "date": "2026/4/8", "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": "CA125593/MONDO:0100562/173/ci/CA125593/MONDO:0100562/173.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA125593/MONDO:0100562/173/0/1648/1650", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA125593/MONDO:0100562/173/1/1649", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA125593/MONDO:0100562/173/0/1648", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA125593/MONDO:0100562/173/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA125593/MONDO:0100562/173/ei/1/1748", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50052_EP177555712278789", "id": "CG-PCER-AGENT:CG_50052_EP177555712278789", "type": "Agent" }, "contributionDate": { "date": "2026/4/8", "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/CA125593/MONDO:0100562/173/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA125593/MONDO:0100562/173/ci/CA125593/MONDO:0100562/173.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50052_EP177555712278789", "id": "CG-PCER-AGENT:CG_50052_EP177555712278789", "type": "Agent" }, "comments": "The computational predictor REVEL gives a score of 0.91, which is above the threshold of 0.8, evidence that correlates with impact to HBA2 function.", "contributionDate": { "date": "2026/4/8", "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": "CA125593/MONDO:0100562/173/ci/CA125593/MONDO:0100562/173.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA125593/MONDO:0100562/173/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA125593/MONDO:0100562/173/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA125593/MONDO:0100562/173/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA125593/MONDO:0100562/173/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA125593/MONDO:0100562/173/ei/1/1637", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50052_EP177555712278789", "id": "CG-PCER-AGENT:CG_50052_EP177555712278789", "type": "Agent" }, "contributionDate": { "date": "2026/4/8", "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/CA125593/MONDO:0100562/173/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA125593/MONDO:0100562/173/ci/CA125593/MONDO:0100562/173.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50052_EP177555712278789", "id": "CG-PCER-AGENT:CG_50052_EP177555712278789", "type": "Agent" }, "comments": "The minor allele frequency in gnomAD v4.1 is 0.0000022 (1/446884 alleles), which is lower than the ClinGen Hemoglobinopathy VCEP threshold <0.0001 for PM2_Supporting, and therefore meets this criterion [PM2_P].", "contributionDate": { "date": "2026/4/8", "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": "CA125593/MONDO:0100562/173/ci/CA125593/MONDO:0100562/173.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA125593/MONDO:0100562/173/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA125593/MONDO:0100562/173/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA125593/MONDO:0100562/173/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA125593/MONDO:0100562/173/el/0/1669", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA125593/MONDO:0100562/173/ei/1/1670", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50052_EP177555712278789", "id": "CG-PCER-AGENT:CG_50052_EP177555712278789", "type": "Agent" }, "contributionDate": { "date": "2026/4/8", "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/CA125593/MONDO:0100562/173/el/0/1669/1671", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA125593/MONDO:0100562/173/ci/CA125593/MONDO:0100562/173.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50052_EP177555712278789", "id": "CG-PCER-AGENT:CG_50052_EP177555712278789", "type": "Agent" }, "comments": "This variant has been detected in 9 individuals with severe clinical phenotype characterized by HbH inclusions and need for transfusion and splenectomy. Of those individuals, 7 were compound heterozygous for the variant and a pathogenic variant and were confirmed in trans by family studies, and 2 individuals were homozygous for the variant. Total PM3 points are 8 [PMID: 20854116; 29219637; 18473239]\n", "contributionDate": { "date": "2026/4/8", "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": "CA125593/MONDO:0100562/173/ci/CA125593/MONDO:0100562/173.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA125593/MONDO:0100562/173/0/1669/1671", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA125593/MONDO:0100562/173/1/1670", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA125593/MONDO:0100562/173/0/1669", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA125593/MONDO:0100562/173/el/0/1615", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA125593/MONDO:0100562/173/ei/1/1616", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50052_EP177555712278789", "id": "CG-PCER-AGENT:CG_50052_EP177555712278789", "type": "Agent" }, "contributionDate": { "date": "2026/4/8", "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/CA125593/MONDO:0100562/173/el/0/1615/1617", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA125593/MONDO:0100562/173/ci/CA125593/MONDO:0100562/173.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50052_EP177555712278789", "id": "CG-PCER-AGENT:CG_50052_EP177555712278789", "type": "Agent" }, "comments": "This variant does not reside within a region of HBA2 that is defined as a mutational hotspot and/or critical functional domain by the ClinGen Hemoglobinopathy VCEP.", "contributionDate": { "date": "2026/4/8", "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": "CA125593/MONDO:0100562/173/ci/CA125593/MONDO:0100562/173.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA125593/MONDO:0100562/173/0/1615/1617", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA125593/MONDO:0100562/173/1/1616", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA125593/MONDO:0100562/173/0/1615", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA125593/MONDO:0100562/173", "metadata": { "created": "2026-04-08T14:42:51.789Z", "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": "Wed, 08 Apr 2026 14:42:50 -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": "29bc99e3-6288-43e4-9650-419a4e857e56", "variant": { "@id": "https://reg.genome.network/allele/CA125593", "id": "CAR:CA125593", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000517.6:c.89T>C" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000517.6(HBA2):c.89T>C (p.Leu30Pro)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-10-22T19:58:13.829Z" } }, "status": { "code": 200, "name": "OK" } }