{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/c89cc531-8b5f-4912-b847-d76d082aaf68/doc/sepio/version/1.0.0", "assertionMethod": { "@id": "https://cspec.genome.network/cspec/SequenceVariantInterpretation/id/1567863456", "label": "ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RAG2 Version 1.0.0", "type": "VariantPathogenicityInterpretationGuideline", "version": "1.0.0" }, "condition": { "@id": "https://api.monarchinitiative.org/api/bioentity/phenotype/MONDO:0000573", "id": "MONDO:0000573", "label": "recombinase activating gene 2 deficiency", "type": "GeneticCondition" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA1964194540/MONDO:0000573/124/el/0/1615", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA1964194540/MONDO:0000573/124/ei/1/1616", "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/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/CA1964194540/MONDO:0000573/124/el/0/1615/1617", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA1964194540/MONDO:0000573/124/ci/CA1964194540/MONDO:0000573/124.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50091_EP170474596929316", "id": "CG-PCER-AGENT:CG_50091_EP170474596929316", "type": "Agent" }, "comments": "only for missense variants", "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": "CA1964194540/MONDO:0000573/124/ci/CA1964194540/MONDO:0000573/124.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA1964194540/MONDO:0000573/124/0/1615/1617", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA1964194540/MONDO:0000573/124/1/1616", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA1964194540/MONDO:0000573/124/0/1615", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA1964194540/MONDO:0000573/124/el/0/1717", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA1964194540/MONDO:0000573/124/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/CA1964194540/MONDO:0000573/124/el/0/1717/1719", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA1964194540/MONDO:0000573/124/ci/CA1964194540/MONDO:0000573/124.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50091_EP170474596929316", "id": "CG-PCER-AGENT:CG_50091_EP170474596929316", "type": "Agent" }, "comments": "Variant co-occurs with p.Phe183Asn (phase unknown) in SCID patient PA30 (PMID: 24144642). Variant co-occurs with p.E170G (likely trans but only mother tested so phase not completely confirmed) in patient with later onset CID phenotype (PMID: 31058115). Neither p.Phe183Asn nor p.E170G have yet been curated by ClinGen SCID VCEP. Since phase not confirmed, even if both variants turn out to be P, the max awarded would be 0.5p per proband (1p), so it's possible that PM3 could be applied at regular strength (no modification) in future but that's only IF both co-occurring variants turned out to be fully pathogenic.", "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": "CA1964194540/MONDO:0000573/124/ci/CA1964194540/MONDO:0000573/124.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA1964194540/MONDO:0000573/124/0/1717/1719", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA1964194540/MONDO:0000573/124/1/1718", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA1964194540/MONDO:0000573/124/0/1717", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA1964194540/MONDO:0000573/124/el/0/1594", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA1964194540/MONDO:0000573/124/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/CA1964194540/MONDO:0000573/124/el/0/1594/1596", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA1964194540/MONDO:0000573/124/ci/CA1964194540/MONDO:0000573/124.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50091_EP170474596929316", "id": "CG-PCER-AGENT:CG_50091_EP170474596929316", "type": "Agent" }, "comments": "The c.829dup variant is a frameshift variant (p.Tyr277Leufs*4) with an expected premature termination codon at p.279. The total number of amino acids is 528, so although this variant would be expected to escape NMD (RAG2 has only a single coding exon), approximately 47% of the total protein would be deleted. In addition, this variant would be expected to delete the entire PHD domain (amino acids 414-487), which is a critical region for protein function (PMID: 15964836). PVS1 met.", "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": "CA1964194540/MONDO:0000573/124/ci/CA1964194540/MONDO:0000573/124.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA1964194540/MONDO:0000573/124/0/1594/1596", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA1964194540/MONDO:0000573/124/1/1595", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA1964194540/MONDO:0000573/124/0/1594", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA1964194540/MONDO:0000573/124/el/0/1633", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA1964194540/MONDO:0000573/124/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/CA1964194540/MONDO:0000573/124/el/0/1633/1635", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA1964194540/MONDO:0000573/124/ci/CA1964194540/MONDO:0000573/124.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50091_EP170474596929316", "id": "CG-PCER-AGENT:CG_50091_EP170474596929316", "type": "Agent" }, "comments": "I have counted the SCID patient in PMID: 24144642 as meeting PP4 though it may be a bit of a stretch: Everyone in cohort seems to have T-B-NK+ SCID and everyone had severe enough disease to undergo HSCT (so I am presuming diagnostic criteria for SCID was met even though this was not explicitly stated in the paper): 0.5p +0.5p = 1p = PP4 met with no modification. Other patients reported do not meet PP4. PMID: 34851571 has diagnosis of Omenn syndrome but only single heterozygous RAG variant reported (no second variant identified). PMID: 31058115 has later onset disease but does not meet SCID or leaky SCID criteria, phenotype more consistent with later onset CID.", "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": "CA1964194540/MONDO:0000573/124/ci/CA1964194540/MONDO:0000573/124.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA1964194540/MONDO:0000573/124/0/1633/1635", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA1964194540/MONDO:0000573/124/1/1634", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA1964194540/MONDO:0000573/124/0/1633", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA1964194540/MONDO:0000573/124/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA1964194540/MONDO:0000573/124/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/CA1964194540/MONDO:0000573/124/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA1964194540/MONDO:0000573/124/ci/CA1964194540/MONDO:0000573/124.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50091_EP170474596929316", "id": "CG-PCER-AGENT:CG_50091_EP170474596929316", "type": "Agent" }, "comments": "Variant is absent in gnomAD", "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": "CA1964194540/MONDO:0000573/124/ci/CA1964194540/MONDO:0000573/124.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA1964194540/MONDO:0000573/124/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA1964194540/MONDO:0000573/124/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA1964194540/MONDO:0000573/124/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA1964194540/MONDO:0000573/124/el/0/1825", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA1964194540/MONDO:0000573/124/ei/1/1826", "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/0039", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000216", "id": "SEPIO:0000216", "label": "Pathogenic Moderate" }, "id": "0039", "label": "PS3", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA1964194540/MONDO:0000573/124/el/0/1825/1827", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA1964194540/MONDO:0000573/124/ci/CA1964194540/MONDO:0000573/124.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50091_EP170474596929316", "id": "CG-PCER-AGENT:CG_50091_EP170474596929316", "type": "Agent" }, "comments": "Recombinase activity of this variant is zero (PMID: 31058115), which meets ClinGen SCID VCEP's criteria for PS3_moderate (< 25% wildtype activity). ", "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": "CA1964194540/MONDO:0000573/124/ci/CA1964194540/MONDO:0000573/124.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA1964194540/MONDO:0000573/124/0/1825/1827", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA1964194540/MONDO:0000573/124/1/1826", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA1964194540/MONDO:0000573/124/0/1825", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA1964194540/MONDO:0000573/124", "metadata": { "created": "2024-09-28T03:42:09.009Z", "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 03:42:08 -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": "c89cc531-8b5f-4912-b847-d76d082aaf68", "variant": { "@id": "https://reg.genome.network/allele/CA1964194540", "id": "CAR:CA1964194540", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000536.4:c.829dup" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000536.4(RAG2):c.829dup (p.Tyr277fs)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-11-11T08:09:15.867Z" } }, "status": { "code": 200, "name": "OK" } }