{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/028ba414-0b6f-44c4-b287-6e3a75e482d0/doc/sepio/version/1.0.0", "assertionMethod": { "@id": "https://cspec.genome.network/cspec/SequenceVariantInterpretation/id/1567643911", "label": "ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RAG1 Version 1.0.0", "type": "VariantPathogenicityInterpretationGuideline", "version": "1.0.0" }, "condition": { "@id": "https://api.monarchinitiative.org/api/bioentity/phenotype/MONDO:0000572", "id": "MONDO:0000572", "label": "recombinase activating gene 1 deficiency", "type": "GeneticCondition" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA5949977/MONDO:0000572/123/el/0/1594", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA5949977/MONDO:0000572/123/ei/1/1595", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50091_EP170474596929316", "id": "CG-PCER-AGENT:CG_50091_EP170474596929316", "type": "Agent" }, "contributionDate": { "date": "2024/1/17", "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/0017", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000220", "id": "SEPIO:0000220", "label": "Pathogenic Very Strong" }, "id": "0017", "label": "PVS1", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA5949977/MONDO:0000572/123/el/0/1594/1596", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA5949977/MONDO:0000572/123/ci/CA5949977/MONDO:0000572/123.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50091_EP170474596929316", "id": "CG-PCER-AGENT:CG_50091_EP170474596929316", "type": "Agent" }, "comments": "Nonsense variant NM_000448.3(RAG1):c.424C>T (p.Arg142Ter) occurs in exon 2 of 2 (the only coding exon of RAG1) and is not predicted to result in NMD but does truncate 86% of the protein, including the entirety of the core domain (amino acids 387-1011) which is critical to protein function (PMID: 26996199; PVS1).", "contributionDate": { "date": "2024/1/17", "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": "CA5949977/MONDO:0000572/123/ci/CA5949977/MONDO:0000572/123.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA5949977/MONDO:0000572/123/0/1594/1596", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA5949977/MONDO:0000572/123/1/1595", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA5949977/MONDO:0000572/123/0/1594", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA5949977/MONDO:0000572/123/el/0/1633", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA5949977/MONDO:0000572/123/ei/1/1634", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50091_EP170474596929316", "id": "CG-PCER-AGENT:CG_50091_EP170474596929316", "type": "Agent" }, "contributionDate": { "date": "2024/1/17", "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/CA5949977/MONDO:0000572/123/el/0/1633/1635", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA5949977/MONDO:0000572/123/ci/CA5949977/MONDO:0000572/123.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50091_EP170474596929316", "id": "CG-PCER-AGENT:CG_50091_EP170474596929316", "type": "Agent" }, "comments": "This variant has been reported in at least seven patients with atypical SCID or Omenn syndrome (PMIDs: 30877075, 33225392, 30307608, 25849362, 20109747, 24290284, 17075247) however in all cases there is insufficient information to determine that the patient's phenotype is highly specific to recombinase activating gene 1 deficiency (PP4_NotMet).", "contributionDate": { "date": "2024/1/17", "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": "CA5949977/MONDO:0000572/123/ci/CA5949977/MONDO:0000572/123.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA5949977/MONDO:0000572/123/0/1633/1635", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA5949977/MONDO:0000572/123/1/1634", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA5949977/MONDO:0000572/123/0/1633", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA5949977/MONDO:0000572/123/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA5949977/MONDO:0000572/123/ei/1/1637", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50091_EP170474596929316", "id": "CG-PCER-AGENT:CG_50091_EP170474596929316", "type": "Agent" }, "contributionDate": { "date": "2024/1/17", "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/CA5949977/MONDO:0000572/123/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA5949977/MONDO:0000572/123/ci/CA5949977/MONDO:0000572/123.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50091_EP170474596929316", "id": "CG-PCER-AGENT:CG_50091_EP170474596929316", "type": "Agent" }, "comments": "The popmax allele frequency is 0.00004007 (1/24954 alleles) in the African/African American population, which is below the SCID VCEP established threshold of <0.000102.", "contributionDate": { "date": "2024/1/17", "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": "CA5949977/MONDO:0000572/123/ci/CA5949977/MONDO:0000572/123.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA5949977/MONDO:0000572/123/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA5949977/MONDO:0000572/123/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA5949977/MONDO:0000572/123/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA5949977/MONDO:0000572/123/el/0/1828", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA5949977/MONDO:0000572/123/ei/1/1829", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50091_EP170474596929316", "id": "CG-PCER-AGENT:CG_50091_EP170474596929316", "type": "Agent" }, "contributionDate": { "date": "2024/1/17", "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/0052", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000330", "id": "SEPIO:0000330", "label": "Pathogenic Strong" }, "id": "0052", "label": "PS3", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA5949977/MONDO:0000572/123/el/0/1828/1830", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA5949977/MONDO:0000572/123/ci/CA5949977/MONDO:0000572/123.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50091_EP170474596929316", "id": "CG-PCER-AGENT:CG_50091_EP170474596929316", "type": "Agent" }, "comments": "A-MuLV– transformed Rag1−/− tg.Eμ-bcl2 pro-B cells, containing a single integration of the pMX-INV GFP cassette flanked by RSSs, which were further transduced with retroviral vectors encoding wild-type or mutant hRAG1 or wild-type mouse Rag1 (mRag1) and hCD2 as a reporter. VDJ recombination activity was measured by normalizing GFP expression to that observed in the presence of wild-type hRAG1. Mean recombination activity for Arg142Ter was 9.0% of wild type +/- 4.0 (PMID: 24290284; PS3_moderate). However, because no patient has been identified meeting the PP4 criteria PS3 is not applied at any strength.", "contributionDate": { "date": "2024/1/17", "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": "CA5949977/MONDO:0000572/123/ci/CA5949977/MONDO:0000572/123.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA5949977/MONDO:0000572/123/0/1828/1830", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA5949977/MONDO:0000572/123/1/1829", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA5949977/MONDO:0000572/123/0/1828", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA5949977/MONDO:0000572/123/el/0/1717", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA5949977/MONDO:0000572/123/ei/1/1718", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50091_EP170474596929316", "id": "CG-PCER-AGENT:CG_50091_EP170474596929316", "type": "Agent" }, "contributionDate": { "date": "2024/1/17", "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/007", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000216", "id": "SEPIO:0000216", "label": "Pathogenic Moderate" }, "id": "007", "label": "PM3", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA5949977/MONDO:0000572/123/el/0/1717/1719", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA5949977/MONDO:0000572/123/ci/CA5949977/MONDO:0000572/123.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50091_EP170474596929316", "id": "CG-PCER-AGENT:CG_50091_EP170474596929316", "type": "Agent" }, "comments": "This variant has been reported homozygous in at least two Omenn syndrome patients (PMIDs: 33225392, 30307608; 1pt; PM3). Five additional atypical SCID or Omenn syndrome cases have been reported compound heterozygous for this variant (PMIDs: 30877075, 25849362, 20109747, 24290284, 17075247). The second variant in these cases have not yet been classified by the ClinGen SCID VCEP: Thr477Ser, M458SfsX34, and R396H (potential to score 0-0.5pt each), as well as Val779Met (potential to score 0.25-1pt) and are not considered here to avoid circularity.", "contributionDate": { "date": "2024/1/17", "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": "CA5949977/MONDO:0000572/123/ci/CA5949977/MONDO:0000572/123.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA5949977/MONDO:0000572/123/0/1717/1719", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA5949977/MONDO:0000572/123/1/1718", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA5949977/MONDO:0000572/123/0/1717", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA5949977/MONDO:0000572/123", "metadata": { "created": "2024-09-28T03:41:54.589Z", "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": "Sat, 28 Sep 2024 03:41:54 -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": "028ba414-0b6f-44c4-b287-6e3a75e482d0", "variant": { "@id": "https://reg.genome.network/allele/CA5949977", "id": "CAR:CA5949977", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000448.3:c.424C>T" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000448.3(RAG1):c.424C>T (p.Arg142Ter)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-10-14T15:07:07.770Z" } }, "status": { "code": 200, "name": "OK" } }