{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/48d993da-ab40-4a8c-bb8c-f7e2242d48a4/doc/sepio/version/1.0.0", "assertionMethod": { "@id": "https://cspec.genome.network/cspec/SequenceVariantInterpretation/id/1564418400", "label": "ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ADA Version 2.1.0", "type": "VariantPathogenicityInterpretationGuideline", "version": "2.1.0" }, "condition": { "@id": "https://api.monarchinitiative.org/api/bioentity/phenotype/MONDO:0007064", "id": "MONDO:0007064", "label": "adenosine deaminase deficiency", "type": "GeneticCondition" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA266005/MONDO:0007064/114/el/0/1696", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA266005/MONDO:0007064/114/ei/1/1697", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50091_EP170474596929316", "id": "CG-PCER-AGENT:CG_50091_EP170474596929316", "type": "Agent" }, "contributionDate": { "date": "2025/11/21", "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/CA266005/MONDO:0007064/114/el/0/1696/1698", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA266005/MONDO:0007064/114/ci/CA266005/MONDO:0007064/114.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50091_EP170474596929316", "id": "CG-PCER-AGENT:CG_50091_EP170474596929316", "type": "Agent" }, "comments": "% wild type =0.11+/0.4 Group II PMID 9758612\nThe strength of evidence from cellular models/in vitro studies is dependent upon the level of expressed ADA enzyme activity based on levels defined in Arredondo-Vega et al., 1998 (PMID: 9758612):meets SCID VCEP PS3_Supporting criteria for PS3_Supporting.", "contributionDate": { "date": "2025/11/21", "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": "CA266005/MONDO:0007064/114/ci/CA266005/MONDO:0007064/114.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA266005/MONDO:0007064/114/0/1696/1698", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA266005/MONDO:0007064/114/1/1697", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA266005/MONDO:0007064/114/0/1696", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA266005/MONDO:0007064/114/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA266005/MONDO:0007064/114/ei/1/1748", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50091_EP170474596929316", "id": "CG-PCER-AGENT:CG_50091_EP170474596929316", "type": "Agent" }, "contributionDate": { "date": "2025/11/21", "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/CA266005/MONDO:0007064/114/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA266005/MONDO:0007064/114/ci/CA266005/MONDO:0007064/114.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50091_EP170474596929316", "id": "CG-PCER-AGENT:CG_50091_EP170474596929316", "type": "Agent" }, "comments": "Cannot be applied to mis-sense variants as per SCID VCEP recommendations.", "contributionDate": { "date": "2025/11/21", "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": "CA266005/MONDO:0007064/114/ci/CA266005/MONDO:0007064/114.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA266005/MONDO:0007064/114/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA266005/MONDO:0007064/114/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA266005/MONDO:0007064/114/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA266005/MONDO:0007064/114/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA266005/MONDO:0007064/114/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": "2025/11/21", "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/CA266005/MONDO:0007064/114/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA266005/MONDO:0007064/114/ci/CA266005/MONDO:0007064/114.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50091_EP170474596929316", "id": "CG-PCER-AGENT:CG_50091_EP170474596929316", "type": "Agent" }, "comments": "The Grpmax filtering allele frequency of the NM_000022.4(ADA):c.385G>A (p.Val129Met) variant is 0.00000187 by gnomAD v4.1.0, which is lower than the ClinGen SCID VCEP threshold (<0.000115) for PM2_Supporting. Additionally, no homozygotes have been observed. (PM2_Supporting). ", "contributionDate": { "date": "2025/11/21", "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": "CA266005/MONDO:0007064/114/ci/CA266005/MONDO:0007064/114.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA266005/MONDO:0007064/114/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA266005/MONDO:0007064/114/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA266005/MONDO:0007064/114/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA266005/MONDO:0007064/114/el/0/1669", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA266005/MONDO:0007064/114/ei/1/1670", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50091_EP170474596929316", "id": "CG-PCER-AGENT:CG_50091_EP170474596929316", "type": "Agent" }, "contributionDate": { "date": "2025/11/21", "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/CA266005/MONDO:0007064/114/el/0/1669/1671", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA266005/MONDO:0007064/114/ci/CA266005/MONDO:0007064/114.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50091_EP170474596929316", "id": "CG-PCER-AGENT:CG_50091_EP170474596929316", "type": "Agent" }, "comments": "Internal communication with Dr. Michael Hershfield indicated there are records of 2 homozygous patients with a delayed-onset CID phenotype-one cared for in Ottawa Canada and the other in Boston.  Both patients are ADA- deficient and have elevated levels of red cell dAXP. One of these cases may correspond to the patient described in PMID: 32888943, given that the authors are also from Boston (1 point). This variant was also found in the homozygous state in three additional unrelated ADA-deficient probands (3 points; PMID: 31858364, 26255240). In addition, this variant was identified in compound heterozygous state in five unrelated ADA-deficient probands. The accompanying missense ADA variants were Gly140Arg (c.418G>A), Ser291Leu (c.872C>T), His15Asp (c.43C>G) and two variants not specified. The ADA variant Ser291Leu has been classified as likely pathogenic by the SCID expert panel, while the other two are VUS (1.5 points; PMID: 39052144, 32307643, 26376800 ). In total, the evidence sums to 5.5 points, therefore, PM3_very strong is met. \n", "contributionDate": { "date": "2025/11/21", "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": "CA266005/MONDO:0007064/114/ci/CA266005/MONDO:0007064/114.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA266005/MONDO:0007064/114/0/1669/1671", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA266005/MONDO:0007064/114/1/1670", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA266005/MONDO:0007064/114/0/1669", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA266005/MONDO:0007064/114/el/0/1831", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA266005/MONDO:0007064/114/ei/1/1832", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50091_EP170474596929316", "id": "CG-PCER-AGENT:CG_50091_EP170474596929316", "type": "Agent" }, "contributionDate": { "date": "2025/11/21", "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/CA266005/MONDO:0007064/114/el/0/1831/1833", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA266005/MONDO:0007064/114/ci/CA266005/MONDO:0007064/114.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50091_EP170474596929316", "id": "CG-PCER-AGENT:CG_50091_EP170474596929316", "type": "Agent" }, "comments": "2 patients with delayed onset SCID were reported in PMID: 10200056. Patient 'AR' (homozygous) was tested by sequencing cDNA, amplified genomic DNA, SSCP of amplified genomic DNA and pretreatment RBC dAXP.\n* Observed Increased dAdo nucleotides (dATP or dAXP) in pretreatment erythrocytes (5 pt)\n\nTOTAL 5 points PP4_Moderate\n", "contributionDate": { "date": "2025/11/21", "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": "CA266005/MONDO:0007064/114/ci/CA266005/MONDO:0007064/114.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA266005/MONDO:0007064/114/0/1831/1833", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA266005/MONDO:0007064/114/1/1832", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA266005/MONDO:0007064/114/0/1831", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA266005/MONDO:0007064/114", "metadata": { "created": "2025-11-21T15:53:29.549Z", "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": "Fri, 21 Nov 2025 15:53:29 -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": "48d993da-ab40-4a8c-bb8c-f7e2242d48a4", "variant": { "@id": "https://reg.genome.network/allele/CA266005", "id": "CAR:CA266005", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000022.4:c.385G>A" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000022.4(ADA):c.385G>A (p.Val129Met)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-10-14T10:42:52.855Z" } }, "status": { "code": 200, "name": "OK" } }