{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/2f48c5f4-68d9-47cc-957b-e806dfa20731/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/CA276414731/MONDO:0100562/173/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA276414731/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/CA276414731/MONDO:0100562/173/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA276414731/MONDO:0100562/173/ci/CA276414731/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 0.867, 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": "CA276414731/MONDO:0100562/173/ci/CA276414731/MONDO:0100562/173.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA276414731/MONDO:0100562/173/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA276414731/MONDO:0100562/173/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA276414731/MONDO:0100562/173/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA276414731/MONDO:0100562/173/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA276414731/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/CA276414731/MONDO:0100562/173/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA276414731/MONDO:0100562/173/ci/CA276414731/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 8.741e-7 (1/1143980) 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": "CA276414731/MONDO:0100562/173/ci/CA276414731/MONDO:0100562/173.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA276414731/MONDO:0100562/173/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA276414731/MONDO:0100562/173/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA276414731/MONDO:0100562/173/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA276414731/MONDO:0100562/173/el/0/1606", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA276414731/MONDO:0100562/173/ei/1/1607", "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/CA276414731/MONDO:0100562/173/el/0/1606/1608", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA276414731/MONDO:0100562/173/ci/CA276414731/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 5 unrelated probands meeting low MCV and low MCH, and in 2 unrelated probands meeting low MCV, low MCH and normal red blood cell counts (RBC). Total score is 1.15 (PMID:20642338; PMID: 24351118; PMID: 24829075).\n\nPMID:20642338\nFamily 1: 1-1 (MCV=75.3; MCH=25.8) 1-2 (MCH=63.5; MCH=21.3) => 0.15x2 = 0.3\nFamily 2: 1-1 (MCV=75.8; MCH=25.2) => 0.15x1 = 0.15\nFamily 3: 1-1 (MCV=75.3; MCH=24.1) 1-2 (MCH=71.4; MCH=23.4) => 0.15x2 = 0.3\n\nPMID: 24351118\nMother: Low (MCV=68.8; MCH=23.4), normal RBC (5.04x10^12/L) => 0.2\n\nPMID: 24829075\nFamily 1: Dad: Low (MCV=74.3; MCH=23.6), normal RBC (5.21), anemic (Hb: 12.3gd/L) => 0.2\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": "CA276414731/MONDO:0100562/173/ci/CA276414731/MONDO:0100562/173.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA276414731/MONDO:0100562/173/0/1606/1608", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA276414731/MONDO:0100562/173/1/1607", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA276414731/MONDO:0100562/173/0/1606", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA276414731/MONDO:0100562/173/el/0/1669", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA276414731/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/CA276414731/MONDO:0100562/173/el/0/1669/1671", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA276414731/MONDO:0100562/173/ci/CA276414731/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 12 individuals with alpha thalassemia and in 1 individual with HbH. All individuals were compound heterozygous for the variant (Hb Adana) and a pathogenic variant (Hb CS), and were confirmed in trans by family testing and by DNA studies. Total PM3 points are 13 (PMID:27271331; PMID: 24829075; ClinVar SCVs: 15624; Hemoglobin VCEP).\n\nPMID:27271331\n- Eleven (11) cases (P2-P12) with severe α-thalassemia (chronic hemolytic anemia, transfusion dependent, hepatosplenomegaly, conjugated bilirubin, jaundice)\n-\tIn trans with Hb constant spring (αCSα)\n-\tCS interpreted as pathogenic based on VCEP classification\n- CS excluded from “PM3 requiring PM2_P” to be met\n\nPMID: 24829075\n-\tFamily A: Two (2) affected individuals (anemia, hepatosplenomegaly, MCV=84.6, MCH=25.6, HbA2=2.3; MCV=75.6, MCH=23.4. HbA2=2.3)\n-\tIn trans with Hb constant spring (αCSα)\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": "CA276414731/MONDO:0100562/173/ci/CA276414731/MONDO:0100562/173.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA276414731/MONDO:0100562/173/0/1669/1671", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA276414731/MONDO:0100562/173/1/1670", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA276414731/MONDO:0100562/173/0/1669", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA276414731/MONDO:0100562/173/el/0/1648", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA276414731/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/CA276414731/MONDO:0100562/173/el/0/1648/1650", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA276414731/MONDO:0100562/173/ci/CA276414731/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 alpha thalassemia in 2 affected members (αp.Gly60Aspα/-α3.7) and with HbH (αp.Gly60Aspα/--SEA) in one affected member from one family. The total number of unaffected segregations (did not inherit Hb Adana) is 3. The LOD score is 2.18 (PMID: 24829075). \n\nPMID: 24829075\nThree affected individuals \no\tTwo probands: low (MCV=76.7, MCH=24.7, HbA2=2.0; MCV=75.4, MCH=24.0, HbA2=2.1), Clinically pale, splenomegaly, history of anemia, intermittent jaundice, seldom blood transfusion.\no\tPhenotype more severe than parent carriers: in trans with a3.7del ( /-a3.7) \no\tOne stillborn hydropic fetus: in trans with SEAdel\n\nThree unaffected: did not inherit Hb Adana.\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": "CA276414731/MONDO:0100562/173/ci/CA276414731/MONDO:0100562/173.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA276414731/MONDO:0100562/173/0/1648/1650", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA276414731/MONDO:0100562/173/1/1649", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA276414731/MONDO:0100562/173/0/1648", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA276414731/MONDO:0100562/173/el/0/1786", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA276414731/MONDO:0100562/173/ei/1/1787", "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/CA276414731/MONDO:0100562/173/el/0/1786/1788", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA276414731/MONDO:0100562/173/ci/CA276414731/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 same amino acid change p.Gly60Asp, resulting from the same nucleotide change c.179G>A [ClinVar: 15849] is classified as pathogenic in HBA1 for Alpha thalassemia with a 2 star review status by ClinVar.", "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": "CA276414731/MONDO:0100562/173/ci/CA276414731/MONDO:0100562/173.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA276414731/MONDO:0100562/173/0/1786/1788", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA276414731/MONDO:0100562/173/1/1787", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA276414731/MONDO:0100562/173/0/1786", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA276414731/MONDO:0100562/173/el/0/1780", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA276414731/MONDO:0100562/173/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": "2026/4/8", "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/CA276414731/MONDO:0100562/173/el/0/1780/1782", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA276414731/MONDO:0100562/173/ci/CA276414731/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": "Another missense variant c.178G>C, p.(Gly60Arg) in the same codon has been reported in a patient with alpha thalassemia (ClinVar ID: 15688). However, this variant has not yet met the criteria to be classified as pathogenic with a 2-star review status by ClinVar.", "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": "CA276414731/MONDO:0100562/173/ci/CA276414731/MONDO:0100562/173.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA276414731/MONDO:0100562/173/0/1780/1782", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA276414731/MONDO:0100562/173/1/1781", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA276414731/MONDO:0100562/173/0/1780", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA276414731/MONDO:0100562/173", "metadata": { "created": "2026-04-08T06:29:03.071Z", "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 06:29:02 -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": "2f48c5f4-68d9-47cc-957b-e806dfa20731", "variant": { "@id": "https://reg.genome.network/allele/CA276414731", "id": "CAR:CA276414731", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000517.6:c.179G>A" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000517.6(HBA2):c.179G>A (p.Gly60Asp)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-10-22T20:00:56.657Z" } }, "status": { "code": 200, "name": "OK" } }