{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/0de45bdb-5b58-432f-b6b3-902e15ac59c5/doc/sepio/version/1.0.0", "assertionMethod": { "type": "VariantPathogenicityInterpretationGuideline" }, "condition": { "@id": "https://api.monarchinitiative.org/api/bioentity/phenotype/MONDO:0013144", "id": "MONDO:0013144", "label": "antithrombin III deficiency", "type": "GeneticCondition" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA1251411/MONDO:0013144/084/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA1251411/MONDO:0013144/084/ei/1/1748", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50064_EP169601587241724", "id": "CG-PCER-AGENT:CG_50064_EP169601587241724", "type": "Agent" }, "contributionDate": { "date": "2024/2/19", "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/0062", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000329", "id": "SEPIO:0000329", "label": "Pathogenic Supporting" }, "id": "0062", "label": "PP3", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA1251411/MONDO:0013144/084/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA1251411/MONDO:0013144/084/ci/CA1251411/MONDO:0013144/084.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50064_EP169601587241724", "id": "CG-PCER-AGENT:CG_50064_EP169601587241724", "type": "Agent" }, "contributionDate": { "date": "2024/2/19", "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": "CA1251411/MONDO:0013144/084/ci/CA1251411/MONDO:0013144/084.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA1251411/MONDO:0013144/084/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA1251411/MONDO:0013144/084/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA1251411/MONDO:0013144/084/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA1251411/MONDO:0013144/084/el/0/1633", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA1251411/MONDO:0013144/084/ei/1/1634", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50064_EP169601587241724", "id": "CG-PCER-AGENT:CG_50064_EP169601587241724", "type": "Agent" }, "contributionDate": { "date": "2024/2/19", "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/CA1251411/MONDO:0013144/084/el/0/1633/1635", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA1251411/MONDO:0013144/084/ci/CA1251411/MONDO:0013144/084.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50064_EP169601587241724", "id": "CG-PCER-AGENT:CG_50064_EP169601587241724", "type": "Agent" }, "comments": "Proband diagnosed at age 25. AT activity was measured on 2 different samples: 63% and 61%. No thrombotic events, 1 miscarriage + 1 pregnancy complicated by preeclampsia. ", "contributionDate": { "date": "2024/2/19", "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": "CA1251411/MONDO:0013144/084/ci/CA1251411/MONDO:0013144/084.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA1251411/MONDO:0013144/084/0/1633/1635", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA1251411/MONDO:0013144/084/1/1634", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA1251411/MONDO:0013144/084/0/1633", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA1251411/MONDO:0013144/084/el/0/1684", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA1251411/MONDO:0013144/084/ei/1/1685", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50064_EP169601587241724", "id": "CG-PCER-AGENT:CG_50064_EP169601587241724", "type": "Agent" }, "contributionDate": { "date": "2024/2/19", "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/0080", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000327", "id": "SEPIO:0000327", "label": "Benign Supporting" }, "id": "0080", "label": "BP4", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA1251411/MONDO:0013144/084/el/0/1684/1686", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA1251411/MONDO:0013144/084/ci/CA1251411/MONDO:0013144/084.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50064_EP169601587241724", "id": "CG-PCER-AGENT:CG_50064_EP169601587241724", "type": "Agent" }, "comments": "REVEL score of 0.242 is below the set threshold (>0.6) for this criterion. No splicing disruption prediction per SpliceAI and varSEAK. ", "contributionDate": { "date": "2024/2/19", "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": "CA1251411/MONDO:0013144/084/ci/CA1251411/MONDO:0013144/084.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA1251411/MONDO:0013144/084/0/1684/1686", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA1251411/MONDO:0013144/084/1/1685", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA1251411/MONDO:0013144/084/0/1684", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA1251411/MONDO:0013144/084/el/0/1777", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA1251411/MONDO:0013144/084/ei/1/1778", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50064_EP169601587241724", "id": "CG-PCER-AGENT:CG_50064_EP169601587241724", "type": "Agent" }, "contributionDate": { "date": "2024/2/19", "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/0087", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000325", "id": "SEPIO:0000325", "label": "Benign Stand Alone" }, "id": "0087", "label": "BA1", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA1251411/MONDO:0013144/084/el/0/1777/1779", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA1251411/MONDO:0013144/084/ci/CA1251411/MONDO:0013144/084.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50064_EP169601587241724", "id": "CG-PCER-AGENT:CG_50064_EP169601587241724", "type": "Agent" }, "comments": "This variant has a frequency of 0.53% (>0.002 at 99.99% CI w/subpopulation of w/min of 5 alleles) on African American subpopulation with 143 alleles (gnomAD v2.1.1). No homozygotes reported. Variant is a founder in the African population (PMID: 32920809), thus excluded from the application from BA1. ", "contributionDate": { "date": "2024/2/19", "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": "CA1251411/MONDO:0013144/084/ci/CA1251411/MONDO:0013144/084.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA1251411/MONDO:0013144/084/0/1777/1779", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA1251411/MONDO:0013144/084/1/1778", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA1251411/MONDO:0013144/084/0/1777", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA1251411/MONDO:0013144/084/el/0/1735", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA1251411/MONDO:0013144/084/ei/1/1736", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50064_EP169601587241724", "id": "CG-PCER-AGENT:CG_50064_EP169601587241724", "type": "Agent" }, "contributionDate": { "date": "2024/2/19", "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/0053", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000330", "id": "SEPIO:0000330", "label": "Pathogenic Strong" }, "id": "0053", "label": "PS4", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA1251411/MONDO:0013144/084/el/0/1735/1737", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA1251411/MONDO:0013144/084/ci/CA1251411/MONDO:0013144/084.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50064_EP169601587241724", "id": "CG-PCER-AGENT:CG_50064_EP169601587241724", "type": "Agent" }, "comments": "13.5 points - The patients reported as part of this cohort (with African ancestry) had normal antithrombin or slightly reduced antigen levels with a decreased anti-Xa activity (61.8 +/- 9.3%). Activities were also measured with two other different commercial assays (HemosIL Liquid AT and Biophen AT antiIIa) and were normal-higher. Interestingly, authors demonstrated incubation time-dependent reduction in antithrombin activity in the plasma of the patients with the HemosIL assay). \nSpecifically, we have a total 11 individuals without family history (10 females primarily with obstetric complications and 1 male) with antithrombin activity level of <0.8 IU/mL confirmed on 2 different assays (11 points total, 1 per each). P1 has a reported family history of VTE (1 point). Also, one individual from a random pool of 100 subjects of African ancestry with the allele and shown with reduced antithrombin activity (59%) (0.5 points). Genetic analysis also revealed a common haplotype (13 SNV) shared by all carriers of the mutation with significant minor allele frequency differences among Caucasians and Africans. Also, proband diagnosed at age 33, currently age 35. AT activity was measured on 2 different samples: 62% and 63% (1 point). PS4 is met at the very strong level (PS4_VS).\n", "contributionDate": { "date": "2024/2/19", "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": "CA1251411/MONDO:0013144/084/ci/CA1251411/MONDO:0013144/084.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA1251411/MONDO:0013144/084/0/1735/1737", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA1251411/MONDO:0013144/084/1/1736", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA1251411/MONDO:0013144/084/0/1735", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA1251411/MONDO:0013144/084/el/0/1696", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA1251411/MONDO:0013144/084/ei/1/1697", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50064_EP169601587241724", "id": "CG-PCER-AGENT:CG_50064_EP169601587241724", "type": "Agent" }, "contributionDate": { "date": "2024/2/19", "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/0045", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000329", "id": "SEPIO:0000329", "label": "Pathogenic Supporting" }, "id": "0045", "label": "PS3", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA1251411/MONDO:0013144/084/el/0/1696/1698", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA1251411/MONDO:0013144/084/ci/CA1251411/MONDO:0013144/084.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50064_EP169601587241724", "id": "CG-PCER-AGENT:CG_50064_EP169601587241724", "type": "Agent" }, "comments": "In-vitro activity assay of purified recombinant (p.Thr147Ala) protein displayed an anti-Xa activity of approximately 51-55% of the WT recombinant antithrombin in two different commercial assays (Innovance Antithrombin and HemosIL Antithrombin). A reduction in thermal stability was also demonstrated on plasma samples. However, there seems to be no difference in heparin affinity (important as the affected residue hydrogen bonding with residue 79 known to interact with heparin). ", "contributionDate": { "date": "2024/2/19", "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": "CA1251411/MONDO:0013144/084/ci/CA1251411/MONDO:0013144/084.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA1251411/MONDO:0013144/084/0/1696/1698", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA1251411/MONDO:0013144/084/1/1697", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA1251411/MONDO:0013144/084/0/1696", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA1251411/MONDO:0013144/084", "metadata": { "created": "2024-09-28T03:58:45.039Z", "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 03:58:44 -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": "0de45bdb-5b58-432f-b6b3-902e15ac59c5", "variant": { "@id": "https://reg.genome.network/allele/CA1251411", "id": "CAR:CA1251411", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000488.4:c.439A>G" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000488.4(SERPINC1):c.439A>G (p.Thr147Ala)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-11-03T19:27:54.828Z" } }, "status": { "code": 200, "name": "OK" } }