{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/4edf9254-5447-4c2c-981a-dee08ebea662/doc/sepio/version/1.0.0", "assertionMethod": { "@id": "https://cspec.genome.network/cspec/SequenceVariantInterpretation/id/1610842289", "label": "ClinGen Antibody Deficiencies Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PIK3CD Version 1.0.0", "type": "VariantPathogenicityInterpretationGuideline", "version": "1.0.0" }, "condition": { "@id": "https://api.monarchinitiative.org/api/bioentity/phenotype/MONDO:0014222", "id": "MONDO:0014222", "label": "immunodeficiency 14", "type": "GeneticCondition" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA338303812/MONDO:0014222/141/el/0/1780", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA338303812/MONDO:0014222/141/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": "2025/12/23", "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/CA338303812/MONDO:0014222/141/el/0/1780/1782", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA338303812/MONDO:0014222/141/ci/CA338303812/MONDO:0014222/141.002", "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 variant at the same position, NM_005026.5(PIK3CD):c.1573G>A (p.Glu525Lys), has a Grantham’s Distance score (56) lower than the current variant of interest (107) and has been previously classified as pathogenic for immunodeficiency 14 by the ClinGen Antibody Deficiencies VCEP (PM5).", "contributionDate": { "date": "2025/12/23", "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": "CA338303812/MONDO:0014222/141/ci/CA338303812/MONDO:0014222/141.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA338303812/MONDO:0014222/141/0/1780/1782", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA338303812/MONDO:0014222/141/1/1781", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA338303812/MONDO:0014222/141/0/1780", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA338303812/MONDO:0014222/141/el/0/1828", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA338303812/MONDO:0014222/141/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": "2025/12/23", "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/CA338303812/MONDO:0014222/141/el/0/1828/1830", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA338303812/MONDO:0014222/141/ci/EV000001942", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50095_EP176400614458866", "id": "CG-PCER-AGENT:CG_50095_EP176400614458866", "type": "Agent" }, "comments": "Activated T cells from a patient harboring the variant exhibit a 1.4X to 7.9X increase in phosphorylation of AKT at serine 473 and a 1.5X to 4.9X increase in S6 phosphorylation, as demonstrated by western blotting and flow cytometry (PMID: 27426521, Figure 4).", "contributionDate": { "date": "2025/12/23", "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": "CA338303812/MONDO:0014222/141/ci/EV000001942", "traceableAuthorStatement": "https://www.ncbi.nlm.nih.gov/pubmed/27426521", "type": "CuratorInference" } ], "id": "CG-PCER-VARINT:CA338303812/MONDO:0014222/141/0/1828/1830", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA338303812/MONDO:0014222/141/1/1829", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA338303812/MONDO:0014222/141/0/1828", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA338303812/MONDO:0014222/141/el/0/1735", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA338303812/MONDO:0014222/141/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": "2025/12/23", "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/CA338303812/MONDO:0014222/141/el/0/1735/1737", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA338303812/MONDO:0014222/141/ci/CA338303812/MONDO:0014222/141.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50095_EP176400614458866", "id": "CG-PCER-AGENT:CG_50095_EP176400614458866", "type": "Agent" }, "comments": "The proband has accumulated 11 total phenotype points, but has already been used for the PP4 code (PMID: 27426521)", "contributionDate": { "date": "2025/12/23", "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": "CA338303812/MONDO:0014222/141/ci/CA338303812/MONDO:0014222/141.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA338303812/MONDO:0014222/141/0/1735/1737", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA338303812/MONDO:0014222/141/1/1736", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA338303812/MONDO:0014222/141/0/1735", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA338303812/MONDO:0014222/141/el/0/1630", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA338303812/MONDO:0014222/141/ei/1/1631", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50095_EP176400614458866", "id": "CG-PCER-AGENT:CG_50095_EP176400614458866", "type": "Agent" }, "contributionDate": { "date": "2025/12/23", "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/CA338303812/MONDO:0014222/141/el/0/1630/1632", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA338303812/MONDO:0014222/141/ci/CA338303812/MONDO:0014222/141.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50095_EP176400614458866", "id": "CG-PCER-AGENT:CG_50095_EP176400614458866", "type": "Agent" }, "comments": "The variant has been reported to segregate with an APDS phenotype through at least 2 affected meioses from 1 family (PP1_Moderate; PMID: 27426521).", "contributionDate": { "date": "2025/12/23", "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": "CA338303812/MONDO:0014222/141/ci/CA338303812/MONDO:0014222/141.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA338303812/MONDO:0014222/141/0/1630/1632", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA338303812/MONDO:0014222/141/1/1631", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA338303812/MONDO:0014222/141/0/1630", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA338303812/MONDO:0014222/141/el/0/1831", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA338303812/MONDO:0014222/141/ei/1/1832", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50095_EP176400614458866", "id": "CG-PCER-AGENT:CG_50095_EP176400614458866", "type": "Agent" }, "contributionDate": { "date": "2025/12/23", "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/CA338303812/MONDO:0014222/141/el/0/1831/1833", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA338303812/MONDO:0014222/141/ci/CA338303812/MONDO:0014222/141.002", "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 diagnosed with primary immunodeficiency and genotyped by whole exome sequencing excluding causes in other loci, with phenotypes including recurrent lower respiratory tract infections (4 pts), hepatosplenomegaly (4 pts), recurrent herpes infection (3 pts), thrombocytopenia (1 pt), decreased proportion of class-switched memory B cells (1 pt), and increased circulating IgM (0.5 pts), which together are highly specific for APDS (13.5 pts, PMID: 27426521). Additionally, activated T cells from the patient harboring the variant exhibited a 1.4X to 7.9X increase in phosphorylation of AKT at serine 473 and a 1.5X to 4.9X increase in S6 phosphorylation, as demonstrated by western blotting (PMID: 27426521, PP4_Moderate).", "contributionDate": { "date": "2025/12/23", "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": "CA338303812/MONDO:0014222/141/ci/CA338303812/MONDO:0014222/141.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA338303812/MONDO:0014222/141/0/1831/1833", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA338303812/MONDO:0014222/141/1/1832", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA338303812/MONDO:0014222/141/0/1831", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA338303812/MONDO:0014222/141/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA338303812/MONDO:0014222/141/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": "2025/12/23", "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/CA338303812/MONDO:0014222/141/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA338303812/MONDO:0014222/141/ci/CA338303812/MONDO:0014222/141.002", "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 0.393, which is below the ClinGen Antibody Deficiencies VCEP threshold of >0.644 and does not predict a damaging effect on PIK3CD function. The computational predictor CADD gives a PHRED score of 28.0, which is above the ClinGen Antibody Deficiencies VCEP threshold of >25.3 and predicts a deleterious effect on PIK3CD function. Because the two predictors do not agree on a damaging effect, the PP3 code is not met.", "contributionDate": { "date": "2025/12/23", "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": "CA338303812/MONDO:0014222/141/ci/CA338303812/MONDO:0014222/141.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA338303812/MONDO:0014222/141/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA338303812/MONDO:0014222/141/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA338303812/MONDO:0014222/141/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA338303812/MONDO:0014222/141/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA338303812/MONDO:0014222/141/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": "2025/12/23", "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/CA338303812/MONDO:0014222/141/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA338303812/MONDO:0014222/141/ci/CA338303812/MONDO:0014222/141.002", "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": "2025/12/23", "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": "CA338303812/MONDO:0014222/141/ci/CA338303812/MONDO:0014222/141.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA338303812/MONDO:0014222/141/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA338303812/MONDO:0014222/141/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA338303812/MONDO:0014222/141/0/1636", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA338303812/MONDO:0014222/141", "metadata": { "created": "2025-12-23T20:33:03.372Z", "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, 23 Dec 2025 20:33:03 -0000", "schemaLabel": "Evidence Repository.Beta-1 (Unofficial)", "version": "1.0.0" }, "statementOutcome": { "@id": "https://loinc.org/LA26332-9", "id": "LN:LA26332-9", "label": "Likely Pathogenic" }, "type": "VariantPathogenicityInterpretation", "uuid": "4edf9254-5447-4c2c-981a-dee08ebea662", "variant": { "@id": "https://reg.genome.network/allele/CA338303812", "id": "CAR:CA338303812", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_005026.5:c.1574A>C" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_005026.5:c.1574A>C" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-11-01T18:56:57.641Z" } }, "status": { "code": 200, "name": "OK" } }