{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/d8e5dbe0-16a7-4c78-9e02-3bdc8c821832/doc/sepio/version/1.0.0", "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 haploinsuffiency", "type": "GeneticCondition" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138843/MONDO:0014493/122/el/0/1828", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138843/MONDO:0014493/122/ei/1/1829", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50095_EP176400614458866", "id": "CG-PCER-AGENT:CG_50095_EP176400614458866", "type": "Agent" }, "contributionDate": { "date": "2025/12/2", "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/CA350138843/MONDO:0014493/122/el/0/1828/1830", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA350138843/MONDO:0014493/122/ci/CA350138843/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": "RNA sequencing from patient peripheral blood mononuclear cells showed approximately 50% loss of CTLA4 sequencing reads starting 67 base pairs upstream of the 3' end of exon 2, indicating that this variant triggers cryptic splice site usage and a truncated transcript (PMID: 32562209). PS3_Supporting was not met as this evidence was incorporated into the PVS1 code instead.", "contributionDate": { "date": "2025/12/2", "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": "CA350138843/MONDO:0014493/122/ci/CA350138843/MONDO:0014493/122.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA350138843/MONDO:0014493/122/0/1828/1830", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA350138843/MONDO:0014493/122/1/1829", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA350138843/MONDO:0014493/122/0/1828", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138843/MONDO:0014493/122/el/0/1735", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138843/MONDO:0014493/122/ei/1/1736", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50095_EP176400614458866", "id": "CG-PCER-AGENT:CG_50095_EP176400614458866", "type": "Agent" }, "contributionDate": { "date": "2025/12/2", "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/CA350138843/MONDO:0014493/122/el/0/1735/1737", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA350138843/MONDO:0014493/122/ci/CA350138843/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 2 probands, neither of which meets the Antibody Deficiencies VCEP phenotype criteria (PMIDs: 31156616, 29682684).", "contributionDate": { "date": "2025/12/2", "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": "CA350138843/MONDO:0014493/122/ci/CA350138843/MONDO:0014493/122.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA350138843/MONDO:0014493/122/0/1735/1737", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA350138843/MONDO:0014493/122/1/1736", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA350138843/MONDO:0014493/122/0/1735", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138843/MONDO:0014493/122/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138843/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": "2025/12/2", "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/CA350138843/MONDO:0014493/122/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA350138843/MONDO:0014493/122/ci/CA350138843/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 splicing impact predictor SpliceAI gives scores of 0.77 for donor loss and 0.58 for donor gain, which are above the ClinGen Antibody Deficiencies VCEP recommended threshold of ≥0.2 and predict a damaging impact on splicing. PP3 was not met as this evidence was incorporated into the PVS1 code instead.", "contributionDate": { "date": "2025/12/2", "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": "CA350138843/MONDO:0014493/122/ci/CA350138843/MONDO:0014493/122.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA350138843/MONDO:0014493/122/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA350138843/MONDO:0014493/122/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA350138843/MONDO:0014493/122/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138843/MONDO:0014493/122/el/0/1633", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138843/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": "2025/12/2", "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/CA350138843/MONDO:0014493/122/el/0/1633/1635", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA350138843/MONDO:0014493/122/ci/CA350138843/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 a phenotype that included chronic diarrhea (4 pts) with lymphocytic infiltration (1 pt), Kaposi's sarcoma secondary to HHV8 infection (2 pts), neurodevelopmental delay (1 pt), lymphopenia (1 pt), skin findings (1 pt), and arthritis (1 pt), as well as genotyping by whole genome sequencing to rule out an alternative basis for disease in LRBA and DEF6, which together are highly specific for autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency (11 total points, PMID: 32562209, PP4).", "contributionDate": { "date": "2025/12/2", "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": "CA350138843/MONDO:0014493/122/ci/CA350138843/MONDO:0014493/122.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA350138843/MONDO:0014493/122/0/1633/1635", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA350138843/MONDO:0014493/122/1/1634", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA350138843/MONDO:0014493/122/0/1633", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138843/MONDO:0014493/122/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138843/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": "2025/12/2", "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/CA350138843/MONDO:0014493/122/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA350138843/MONDO:0014493/122/ci/CA350138843/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": "2025/12/2", "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": "CA350138843/MONDO:0014493/122/ci/CA350138843/MONDO:0014493/122.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA350138843/MONDO:0014493/122/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA350138843/MONDO:0014493/122/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA350138843/MONDO:0014493/122/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138843/MONDO:0014493/122/el/0/1594", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA350138843/MONDO:0014493/122/ei/1/1595", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50095_EP176400614458866", "id": "CG-PCER-AGENT:CG_50095_EP176400614458866", "type": "Agent" }, "contributionDate": { "date": "2025/12/2", "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/CA350138843/MONDO:0014493/122/el/0/1594/1596", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA350138843/MONDO:0014493/122/ci/CA350138843/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": "NM_005214.5(CTLA4):c.457G>A (p.Asp153Asn) is a variant in the final nucleotide of exon 2. The splicing impact predictor SpliceAI gives scores of 0.77 for donor loss and 0.58 for donor gain, which are above the ClinGen Antibody Deficiencies VCEP recommended threshold of ≥0.2 and predict a damaging impact on splicing. RNA sequencing from patient peripheral blood mononuclear cells showed approximately 50% loss of CTLA4 sequencing reads starting 67 base pairs upstream of the 3' end of exon 2, indicating that this variant triggers cryptic splice site usage and a truncated transcript (PMID: 32562209). PP3 and PS3_Supporting were not met as this predictive and experimental evidence of a splicing defect was incorporated into the PVS1 code instead.", "contributionDate": { "date": "2025/12/2", "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": "CA350138843/MONDO:0014493/122/ci/CA350138843/MONDO:0014493/122.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA350138843/MONDO:0014493/122/0/1594/1596", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA350138843/MONDO:0014493/122/1/1595", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA350138843/MONDO:0014493/122/0/1594", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA350138843/MONDO:0014493/122", "metadata": { "created": "2025-12-02T14:35:14.140Z", "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, 02 Dec 2025 14:35:14 -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": "d8e5dbe0-16a7-4c78-9e02-3bdc8c821832", "variant": { "@id": "https://reg.genome.network/allele/CA350138843", "id": "CAR:CA350138843", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_005214.5:c.457G>A" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_005214.5(CTLA4):c.457G>A (p.Asp153Asn)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-11-01T12:56:23.647Z" } }, "status": { "code": 200, "name": "OK" } }