{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/f5e0c459-540d-4448-82fb-72969aecd4c0/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 2.2", "type": "VariantPathogenicityInterpretationGuideline", "version": "2.2" }, "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/CA274927/MONDO:0007064/114/el/0/1798", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA274927/MONDO:0007064/114/ei/1/1799", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50091_EP170474596929316", "id": "CG-PCER-AGENT:CG_50091_EP170474596929316", "type": "Agent" }, "contributionDate": { "date": "2026/10/27", "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/0011", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000216", "id": "SEPIO:0000216", "label": "Pathogenic Moderate" }, "id": "0011", "label": "PM2", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA274927/MONDO:0007064/114/el/0/1798/1800", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA274927/MONDO:0007064/114/ci/CA274927/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 this variant is 0.00021203 (Non-Finnish European) in gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting for ADA. Therefore, this criterion is not met.", "contributionDate": { "date": "2026/10/27", "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": "CA274927/MONDO:0007064/114/ci/CA274927/MONDO:0007064/114.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA274927/MONDO:0007064/114/0/1798/1800", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA274927/MONDO:0007064/114/1/1799", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA274927/MONDO:0007064/114/0/1798", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA274927/MONDO:0007064/114/el/0/1594", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA274927/MONDO:0007064/114/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": "2026/10/27", "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/CA274927/MONDO:0007064/114/el/0/1594/1596", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA274927/MONDO:0007064/114/ci/CA274927/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": "This is a 5-bp deletion (c.956_960del, p.Glu319Glyfs*3; also reported as c.955_959delAAGAG in older literature) in exon 10, causing a frameshift beginning at codon 319 with a premature termination codon predicted 3 residues downstream (~codon 322). This lies well upstream of the ADA-specific NMD-escape anchor at c.1028 (codon 343, exon 11), so the transcript is predicted to undergo nonsense-mediated decay. This prediction is directly supported by experimental data: Gossage et al. 1993 (PMID 8242080) reported a homozygous patient with \"very low levels of ADA mRNA and protein,\" consistent with NMD, and Santisteban et al. 1993 (PMID 8227344) similarly found this deletion associated with severely reduced corresponding transcript levels in a heterozygous carrier (patient MJ). Therefore, PVS1 was met at full strength.", "contributionDate": { "date": "2026/10/27", "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": "CA274927/MONDO:0007064/114/ci/CA274927/MONDO:0007064/114.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA274927/MONDO:0007064/114/0/1594/1596", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA274927/MONDO:0007064/114/1/1595", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA274927/MONDO:0007064/114/0/1594", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA274927/MONDO:0007064/114/el/0/1738", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA274927/MONDO:0007064/114/ei/1/1739", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50091_EP170474596929316", "id": "CG-PCER-AGENT:CG_50091_EP170474596929316", "type": "Agent" }, "contributionDate": { "date": "2026/10/27", "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/005", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000330", "id": "SEPIO:0000330", "label": "Pathogenic Strong" }, "id": "005", "label": "PP4", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA274927/MONDO:0007064/114/el/0/1738/1740", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA274927/MONDO:0007064/114/ci/CA274927/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": "At least one proband (P3, Cagdas et al. 2018, PMID 29744787) meets diagnostic criteria for SCID with a T-B-NK- phenotype (0.5 pt); has profoundly reduced ADA enzyme activity, undetectable (0 nmol/h/mg), with elevated dAXP (71.9%) (5.0 pts); and presents with a T-B-NK- lymphocyte subset profile (0.5 pt). Total: 6.0 points, meeting PP4_Strong.", "contributionDate": { "date": "2026/10/27", "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": "CA274927/MONDO:0007064/114/ci/CA274927/MONDO:0007064/114.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA274927/MONDO:0007064/114/0/1738/1740", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA274927/MONDO:0007064/114/1/1739", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA274927/MONDO:0007064/114/0/1738", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA274927/MONDO:0007064/114/el/0/1717", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA274927/MONDO:0007064/114/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": "2026/10/27", "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/CA274927/MONDO:0007064/114/el/0/1717/1719", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA274927/MONDO:0007064/114/ci/CA274927/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": "Cagdas et al. 2018 (PMID 29744787) report five unrelated probands homozygous for this variant, reflecting a founder effect in a Turkish cohort. Four probands (P3, P5, P10, P12) have documented consanguinity (0.5 pt each = 2.0 pts), and one proband (P13) is explicitly non-consanguineous (1.0 pt). Total: 3.0 points, meeting PM3_Strong.\nBecause the Grpmax filtering allele frequency of this variant exceeds the PM2_Supporting threshold, PM3 was not applied following SCID-VCEP discussion on 9/25/2026,", "contributionDate": { "date": "2026/10/27", "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": "CA274927/MONDO:0007064/114/ci/CA274927/MONDO:0007064/114.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA274927/MONDO:0007064/114/0/1717/1719", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA274927/MONDO:0007064/114/1/1718", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA274927/MONDO:0007064/114/0/1717", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA274927/MONDO:0007064/114/el/0/1804", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA274927/MONDO:0007064/114/ei/1/1805", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50091_EP170474596929316", "id": "CG-PCER-AGENT:CG_50091_EP170474596929316", "type": "Agent" }, "contributionDate": { "date": "2026/10/27", "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/0070", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000328", "id": "SEPIO:0000328", "label": "Benign Strong" }, "id": "0070", "label": "BS1", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA274927/MONDO:0007064/114/el/0/1804/1806", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA274927/MONDO:0007064/114/ci/CA274927/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 this variant is 0.00021203 (Non-Finnish European) in gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (>0.001611) for BS1. Therefore, this criterion is not met.", "contributionDate": { "date": "2026/10/27", "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": "CA274927/MONDO:0007064/114/ci/CA274927/MONDO:0007064/114.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA274927/MONDO:0007064/114/0/1804/1806", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA274927/MONDO:0007064/114/1/1805", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA274927/MONDO:0007064/114/0/1804", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA274927/MONDO:0007064/114", "metadata": { "created": "2026-10-27T18:31:53.409Z", "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, 27 Oct 2026 18:31:53 -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": "f5e0c459-540d-4448-82fb-72969aecd4c0", "variant": { "@id": "https://reg.genome.network/allele/CA274927", "id": "CAR:CA274927", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000022.4:c.956_960del" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000022.4(ADA):c.956_960del (p.Glu319fs)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-11-04T06:34:30.510Z" } }, "status": { "code": 200, "name": "OK" } }