{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/7031aeab-5c4c-497a-a1bd-d026b0aa03fa/doc/sepio/version/1.1.0", "assertionMethod": { "@id": "https://cspec.genome.network/cspec/SequenceVariantInterpretation/id/1567102241", "label": "ClinGen Antibody Deficiencies Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CTLA4 Version 1.0.0", "type": "VariantPathogenicityInterpretationGuideline", "version": "1.0.0" }, "condition": { "@id": "https://api.monarchinitiative.org/api/bioentity/phenotype/MONDO:0014493", "id": "MONDO:0014493", "label": "autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency", "type": "GeneticCondition" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138732/MONDO:0014493/122/el/0/1615", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138732/MONDO:0014493/122/ei/1/1616", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50095_EP176400614458866", "id": "CG-PCER-AGENT:CG_50095_EP176400614458866", "type": "Agent" }, "contributionDate": { "date": "2026/9/14", "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" } ], "criterion": { "@id": "https://obofoundry.org/sepio/clingen/006", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000216", "id": "SEPIO:0000216", "label": "Pathogenic Moderate" }, "id": "006", "label": "PM1", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138732/MONDO:0014493/122/el/0/1615/1617", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA350138732/MONDO:0014493/122/ci/CA350138732/MONDO:0014493/122.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50095_EP176400614458866", "id": "CG-PCER-AGENT:CG_50095_EP176400614458866", "type": "Agent" }, "comments": "This variant is located within the MYPPPY functional domain (residues 134-139), which is required for interaction with CD80 and CD86 (PM1, PMID: 31396201).", "contributionDate": { "date": "2026/9/14", "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": "CA350138732/MONDO:0014493/122/ci/CA350138732/MONDO:0014493/122.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA350138732/MONDO:0014493/122/0/1615/1617", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA350138732/MONDO:0014493/122/1/1616", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA350138732/MONDO:0014493/122/0/1615", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138732/MONDO:0014493/122/el/0/1780", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138732/MONDO:0014493/122/ei/1/1781", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50095_EP176400614458866", "id": "CG-PCER-AGENT:CG_50095_EP176400614458866", "type": "Agent" }, "contributionDate": { "date": "2026/9/14", "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" } ], "criterion": { "@id": "https://obofoundry.org/sepio/clingen/008", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000216", "id": "SEPIO:0000216", "label": "Pathogenic Moderate" }, "id": "008", "label": "PM5", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138732/MONDO:0014493/122/el/0/1780/1782", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA350138732/MONDO:0014493/122/ci/CA350138732/MONDO:0014493/122.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50095_EP176400614458866", "id": "CG-PCER-AGENT:CG_50095_EP176400614458866", "type": "Agent" }, "comments": "Another missense variants in the same codon, NM_005214.5(CTLA4):c.406C>G (p.Pro136Ala), has a lower Grantham score (27) than the variant under investigation (74) and has been classified as likely pathogenic for autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency by the ClinGen Antibody Deficiencies VCEP (PM5, PMID: 27379089, PMID: 29729943). Splicing prediction using SpliceAI did not strongly predict an effect on splicing due to either of these variants.", "contributionDate": { "date": "2026/9/14", "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": "CA350138732/MONDO:0014493/122/ci/CA350138732/MONDO:0014493/122.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA350138732/MONDO:0014493/122/0/1780/1782", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA350138732/MONDO:0014493/122/1/1781", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA350138732/MONDO:0014493/122/0/1780", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138732/MONDO:0014493/122/el/0/1678", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138732/MONDO:0014493/122/ei/1/1679", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50095_EP176400614458866", "id": "CG-PCER-AGENT:CG_50095_EP176400614458866", "type": "Agent" }, "contributionDate": { "date": "2026/9/14", "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" } ], "criterion": { "@id": "https://obofoundry.org/sepio/clingen/0060", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000329", "id": "SEPIO:0000329", "label": "Pathogenic Supporting" }, "id": "0060", "label": "PP1", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138732/MONDO:0014493/122/el/0/1678/1680", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA350138732/MONDO:0014493/122/ci/CA350138732/MONDO:0014493/122.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50095_EP176400614458866", "id": "CG-PCER-AGENT:CG_50095_EP176400614458866", "type": "Agent" }, "comments": "At least 1 family is available with 1 segregation between the two affected siblings, with the affected status of the second family member confirmed to include hypogammaglobulinemia (2 pts), markedly decreased B-cells (1 pt), multiple episodes of illness including anemia and/or thrombocytopenia, abnormal lymphocyte subsets (1 pt), viral infection (2 pts), and malignancies such as gastric cancer or myelodysplastic syndrome (PMID: 32009323, PP1).", "contributionDate": { "date": "2026/9/14", "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": "CA350138732/MONDO:0014493/122/ci/CA350138732/MONDO:0014493/122.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA350138732/MONDO:0014493/122/0/1678/1680", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA350138732/MONDO:0014493/122/1/1679", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA350138732/MONDO:0014493/122/0/1678", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138732/MONDO:0014493/122/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138732/MONDO:0014493/122/ei/1/1748", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50095_EP176400614458866", "id": "CG-PCER-AGENT:CG_50095_EP176400614458866", "type": "Agent" }, "contributionDate": { "date": "2026/9/14", "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" } ], "criterion": { "@id": "https://obofoundry.org/sepio/clingen/0062", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000329", "id": "SEPIO:0000329", "label": "Pathogenic Supporting" }, "id": "0062", "label": "PP3", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138732/MONDO:0014493/122/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA350138732/MONDO:0014493/122/ci/CA350138732/MONDO:0014493/122.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50095_EP176400614458866", "id": "CG-PCER-AGENT:CG_50095_EP176400614458866", "type": "Agent" }, "comments": "The computational predictor REVEL gives a score of 0.490, which is below the ClinGen Antibody Deficiencies VCEP threshold of >0.75 and does not predict a damaging effect. The computational predictor CADD gives a PHRED score of 24.9, which is above the ClinGen Antibody Deficiencies VCEP threshold of >20 and predicts a damaging effect on CTLA4 function. Because the two predictors do not agree, this criterion is not met. Additionally, the splicing impact predictor SpliceAI gives a score of 0.02 for donor gain, which is below the ClinGen Antibody Deficiencies VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing.", "contributionDate": { "date": "2026/9/14", "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": "CA350138732/MONDO:0014493/122/ci/CA350138732/MONDO:0014493/122.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA350138732/MONDO:0014493/122/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA350138732/MONDO:0014493/122/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA350138732/MONDO:0014493/122/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138732/MONDO:0014493/122/el/0/1633", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138732/MONDO:0014493/122/ei/1/1634", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50095_EP176400614458866", "id": "CG-PCER-AGENT:CG_50095_EP176400614458866", "type": "Agent" }, "contributionDate": { "date": "2026/9/14", "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" } ], "criterion": { "@id": "https://obofoundry.org/sepio/clingen/0063", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000329", "id": "SEPIO:0000329", "label": "Pathogenic Supporting" }, "id": "0063", "label": "PP4", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138732/MONDO:0014493/122/el/0/1633/1635", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA350138732/MONDO:0014493/122/ci/CA350138732/MONDO:0014493/122.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50095_EP176400614458866", "id": "CG-PCER-AGENT:CG_50095_EP176400614458866", "type": "Agent" }, "comments": "This variant has been reported in at least 1 proband with a phenotype that includes autoimmune cytopenias (2 pts), recurrent parotitis (4 pts), autoimmune gastrointestinal findings (4 pts), hepatosplenomegaly (2 pts), and recurrent viral infections (2 pts), with genotyping based on exome sequencing to exclude an alternative basis of disease in other loci such as LRBA, which together is highly specific for autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency (14 pts, PMID: 32009323, PP4).", "contributionDate": { "date": "2026/9/14", "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": "CA350138732/MONDO:0014493/122/ci/CA350138732/MONDO:0014493/122.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA350138732/MONDO:0014493/122/0/1633/1635", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA350138732/MONDO:0014493/122/1/1634", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA350138732/MONDO:0014493/122/0/1633", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138732/MONDO:0014493/122/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138732/MONDO:0014493/122/ei/1/1637", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50095_EP176400614458866", "id": "CG-PCER-AGENT:CG_50095_EP176400614458866", "type": "Agent" }, "contributionDate": { "date": "2026/9/14", "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" } ], "criterion": { "@id": "https://obofoundry.org/sepio/clingen/0030", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000329", "id": "SEPIO:0000329", "label": "Pathogenic Supporting" }, "id": "0030", "label": "PM2", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138732/MONDO:0014493/122/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA350138732/MONDO:0014493/122/ci/CA350138732/MONDO:0014493/122.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50095_EP176400614458866", "id": "CG-PCER-AGENT:CG_50095_EP176400614458866", "type": "Agent" }, "comments": "This variant is absent from gnomAD v4.1.0 (PM2_Supporting).", "contributionDate": { "date": "2026/9/14", "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": "CA350138732/MONDO:0014493/122/ci/CA350138732/MONDO:0014493/122.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA350138732/MONDO:0014493/122/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA350138732/MONDO:0014493/122/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA350138732/MONDO:0014493/122/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138732/MONDO:0014493/122/el/0/1606", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138732/MONDO:0014493/122/ei/1/1607", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50095_EP176400614458866", "id": "CG-PCER-AGENT:CG_50095_EP176400614458866", "type": "Agent" }, "contributionDate": { "date": "2026/9/14", "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" } ], "criterion": { "@id": "https://obofoundry.org/sepio/clingen/0032", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000329", "id": "SEPIO:0000329", "label": "Pathogenic Supporting" }, "id": "0032", "label": "PS4", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138732/MONDO:0014493/122/el/0/1606/1608", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA350138732/MONDO:0014493/122/ci/CA350138732/MONDO:0014493/122.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50095_EP176400614458866", "id": "CG-PCER-AGENT:CG_50095_EP176400614458866", "type": "Agent" }, "comments": "At least one patient harboring this variant had at least 10 phenotypic points, with a phenotype that includes recurrent upper and lower respiratory tract infections (4 pts), enteropathy and diarrhea (4 pts), T cell infiltration of the lung and gut (1 pt), autoimmune thrombocytopenia and autoimmune hemolytic anemia (2 pts), severe viral infection including skin findings (2 pts), recurrent fungal infections (1 pt), splenomegaly and lymphoproliferative disorder (2 pts), decreased circulating IgG level (2 pts), and post-vaccination measles (1 pt), without genotyping to exclude an alternative basis for disease in other loci (PMID: 29729943, PS4_Supporting).", "contributionDate": { "date": "2026/9/14", "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": "CA350138732/MONDO:0014493/122/ci/CA350138732/MONDO:0014493/122.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA350138732/MONDO:0014493/122/0/1606/1608", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA350138732/MONDO:0014493/122/1/1607", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA350138732/MONDO:0014493/122/0/1606", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA350138732/MONDO:0014493/122", "metadata": { "created": "2026-09-14T22:27:31.203Z", "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": "Mon, 14 Sep 2026 22:27:31 -0000", "schemaLabel": "Evidence Repository.Beta-1 (Unofficial)", "version": "1.1.0" }, "statementOutcome": { "@id": "https://loinc.org/LA26332-9", "id": "LN:LA26332-9", "label": "Likely Pathogenic" }, "type": "VariantPathogenicityInterpretation", "uuid": "7031aeab-5c4c-497a-a1bd-d026b0aa03fa", "variant": { "@id": "https://reg.genome.network/allele/CA350138732", "id": "CAR:CA350138732", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_005214.5:c.406C>T" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_005214.5:c.406C>T" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-10-13T23:16:47.511Z" } }, "status": { "code": 200, "name": "OK" } }