{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/16667374-bf76-4afd-a940-8aa7726825fd/doc/sepio/version/1.0.0", "assertionMethod": { "@id": "https://cspec.genome.network/cspec/SequenceVariantInterpretation/id/1745574676", "label": "ClinGen Hemoglobinopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HBB Version 1.0.0", "type": "VariantPathogenicityInterpretationGuideline", "version": "1.0.0" }, "condition": { "@id": "https://api.monarchinitiative.org/api/bioentity/phenotype/MONDO:0013517", "id": "MONDO:0013517", "label": "beta-thalassemia HBB/LCRB", "type": "GeneticCondition" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA125328/MONDO:0013517/170/el/0/1651", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA125328/MONDO:0013517/170/ei/1/1652", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50052_EP177555712278789", "id": "CG-PCER-AGENT:CG_50052_EP177555712278789", "type": "Agent" }, "contributionDate": { "date": "2026/4/7", "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/CA125328/MONDO:0013517/170/el/0/1651/1653", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA125328/MONDO:0013517/170/ci/CA125328/MONDO:0013517/170.002", "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 three individuals with beta thalassemia/major. These individuals are compound heterozygous for the variant (c.78A>C) and pathogenic beta thalassemia and related diseases variants (c.118C>T; c.36del and C.92+1G>A), and were confirmed in trans by family testing. Total PM3 score is 3 (PMID 19960060; PMID: 8619407; internal lab database; ClinVar IDs: 15402; 15423 and 15436)\n\nPMID 19960060: In Trans with pathogenic c.118C>T, p.Gln40Ter (CD 39 C>T): Two stars in ClinVar (ID: 15402): exempt from PM2 requirement\n\nPMID: 8619407: In Trans with pathogenic c.36del, p.Thr13fs (CD 11 (-T): Two stars in ClinVar (ID: 15423): rare in gnomAD\n\nInternal lab database contribution: In trans with pathogenic C.92+1G>A (IVS I-1 G-A): Two stars in ClinVar (ID: 15436): exempt from PM2 requirement.\n", "contributionDate": { "date": "2026/4/7", "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": "CA125328/MONDO:0013517/170/ci/CA125328/MONDO:0013517/170.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA125328/MONDO:0013517/170/0/1651/1653", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA125328/MONDO:0013517/170/1/1652", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA125328/MONDO:0013517/170/0/1651", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA125328/MONDO:0013517/170/el/0/1696", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA125328/MONDO:0013517/170/ei/1/1697", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50052_EP177555712278789", "id": "CG-PCER-AGENT:CG_50052_EP177555712278789", "type": "Agent" }, "contributionDate": { "date": "2026/4/7", "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/CA125328/MONDO:0013517/170/el/0/1696/1698", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA125328/MONDO:0013517/170/ci/CA125328/MONDO:0013517/170.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50052_EP177555712278789", "id": "CG-PCER-AGENT:CG_50052_EP177555712278789", "type": "Agent" }, "comments": "In vitro transcriptional assay and transient expression assay showed 2- to 3-fold decrease in beta globin transcription indicating that this variant impacts protein function (PMID: 2987224). Kinetic studies showed reduced association rate constant and increase dissociation constant of the TATA binding protein (TBP)/TATA box complex also indicating that this variant impacts protein function (PMID: 24616209)", "contributionDate": { "date": "2026/4/7", "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": "CA125328/MONDO:0013517/170/ci/CA125328/MONDO:0013517/170.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA125328/MONDO:0013517/170/0/1696/1698", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA125328/MONDO:0013517/170/1/1697", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA125328/MONDO:0013517/170/0/1696", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA125328/MONDO:0013517/170/el/0/1615", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA125328/MONDO:0013517/170/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": "2026/4/7", "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/CA125328/MONDO:0013517/170/el/0/1615/1617", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA125328/MONDO:0013517/170/ci/CA125328/MONDO:0013517/170.002", "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 resides in a region c.-80 to c.-76 (TATAA box), of HBB that is defined as a mutational hotspot and critical functional domain by the ClinGen Hemoglobinopathy VCEP", "contributionDate": { "date": "2026/4/7", "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": "CA125328/MONDO:0013517/170/ci/CA125328/MONDO:0013517/170.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA125328/MONDO:0013517/170/0/1615/1617", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA125328/MONDO:0013517/170/1/1616", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA125328/MONDO:0013517/170/0/1615", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA125328/MONDO:0013517/170/el/0/1780", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA125328/MONDO:0013517/170/ei/1/1781", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50052_EP177555712278789", "id": "CG-PCER-AGENT:CG_50052_EP177555712278789", "type": "Agent" }, "contributionDate": { "date": "2026/4/7", "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/CA125328/MONDO:0013517/170/el/0/1780/1782", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA125328/MONDO:0013517/170/ci/CA125328/MONDO:0013517/170.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50052_EP177555712278789", "id": "CG-PCER-AGENT:CG_50052_EP177555712278789", "type": "Agent" }, "comments": "Another single nucleotide variant c.-78A>G (ClinVar ID: 15471) in the same base position is considered to have valid evidence for pathogenicity by the VCEP and has been classified as pathogenic for beta thalassemia with a 2-star review status by ClinVar", "contributionDate": { "date": "2026/4/7", "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": "CA125328/MONDO:0013517/170/ci/CA125328/MONDO:0013517/170.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA125328/MONDO:0013517/170/0/1780/1782", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA125328/MONDO:0013517/170/1/1781", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA125328/MONDO:0013517/170/0/1780", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA125328/MONDO:0013517/170/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA125328/MONDO:0013517/170/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": "2026/4/7", "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/CA125328/MONDO:0013517/170/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA125328/MONDO:0013517/170/ci/CA125328/MONDO:0013517/170.002", "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 0.000002948 (3/1017550) alleles, which is lower than the ClinGen Hemoglobinopathy VCEP threshold <0.0001 for PM2_Supporting, and therefore meets this criterion [PM2_P]. ", "contributionDate": { "date": "2026/4/7", "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": "CA125328/MONDO:0013517/170/ci/CA125328/MONDO:0013517/170.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA125328/MONDO:0013517/170/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA125328/MONDO:0013517/170/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA125328/MONDO:0013517/170/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA125328/MONDO:0013517/170/el/0/1678", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA125328/MONDO:0013517/170/ei/1/1679", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50052_EP177555712278789", "id": "CG-PCER-AGENT:CG_50052_EP177555712278789", "type": "Agent" }, "contributionDate": { "date": "2026/4/7", "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/CA125328/MONDO:0013517/170/el/0/1678/1680", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA125328/MONDO:0013517/170/ci/CA125328/MONDO:0013517/170.002", "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 1 affected family member from one family. The total number of unaffected segregations is 0. The LOD score is 0.6 (PMID: 8619407).", "contributionDate": { "date": "2026/4/7", "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": "CA125328/MONDO:0013517/170/ci/CA125328/MONDO:0013517/170.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA125328/MONDO:0013517/170/0/1678/1680", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA125328/MONDO:0013517/170/1/1679", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA125328/MONDO:0013517/170/0/1678", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA125328/MONDO:0013517/170/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA125328/MONDO:0013517/170/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": "2026/4/7", "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/CA125328/MONDO:0013517/170/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA125328/MONDO:0013517/170/ci/CA125328/MONDO:0013517/170.002", "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 CADD gives a PHRED score of 19.52, which is above threshold >12, evidence that correlates with impact to HBB function.", "contributionDate": { "date": "2026/4/7", "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": "CA125328/MONDO:0013517/170/ci/CA125328/MONDO:0013517/170.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA125328/MONDO:0013517/170/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA125328/MONDO:0013517/170/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA125328/MONDO:0013517/170/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA125328/MONDO:0013517/170/el/0/1657", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA125328/MONDO:0013517/170/ei/1/1658", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50052_EP177555712278789", "id": "CG-PCER-AGENT:CG_50052_EP177555712278789", "type": "Agent" }, "contributionDate": { "date": "2026/4/7", "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/CA125328/MONDO:0013517/170/el/0/1657/1659", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA125328/MONDO:0013517/170/ci/CA125328/MONDO:0013517/170.002", "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 13 unrelated individuals with low mcv (67-77.8), low mch (20.5-25.9), and increased HbA2 (4.6-6.3), and in 2 individuals with just low MCV (58.1 and 70) and low MCH (18.2 and 23.3): Total score is 16.3 (PMID 19960060; PMID: 8619407; Internal Lab database)\n\nPMID 19960060; PMID: 8619407:\n2 individuals with low MCV (69 and 69.9), low MCH (21.8 and 20.5) and increased HbA2 (4.8 and 5): 2x1.5=3\n\nInternal lab database contribution:\n11 individuals with low MCV (67-77.8), low MCH (20.5-25.9) and increased HbA2 (4.6-6.3): 11x1.5=16.5=max score is 16 \n2 individuals with low MCV (58.1 and 70), low MCH (18.2 and 23.3): 2x0.15=0.3\n", "contributionDate": { "date": "2026/4/7", "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": "CA125328/MONDO:0013517/170/ci/CA125328/MONDO:0013517/170.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA125328/MONDO:0013517/170/0/1657/1659", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA125328/MONDO:0013517/170/1/1658", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA125328/MONDO:0013517/170/0/1657", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA125328/MONDO:0013517/170", "metadata": { "created": "2026-04-07T14:12:53.441Z", "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": "Tue, 07 Apr 2026 13:54:01 -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": "16667374-bf76-4afd-a940-8aa7726825fd", "variant": { "@id": "https://reg.genome.network/allele/CA125328", "id": "CAR:CA125328", "relatedIdentifier": [ { "label": "NM_000518.5(HBB):c.-78A>C" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-11-05T02:25:47.288Z" } }, "status": { "code": 200, "name": "OK" } }