{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/a227d34e-93cb-4314-936d-5711bf74115f/doc/sepio/version/1.0.0", "assertionMethod": { "@id": "https://cspec.genome.network/cspec/SequenceVariantInterpretation/id/1537428517", "label": "ClinGen Peroxisomal Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ABCD1 Version 1.0.0", "type": "VariantPathogenicityInterpretationGuideline", "version": "1.0.0" }, "condition": { "@id": "https://api.monarchinitiative.org/api/bioentity/phenotype/MONDO:0018544", "id": "MONDO:0018544", "label": "adrenoleukodystrophy", "type": "GeneticCondition" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA121420/MONDO:0018544/105/el/0/1648", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA121420/MONDO:0018544/105/ei/1/1649", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50049_EP177618055787822", "id": "CG-PCER-AGENT:CG_50049_EP177618055787822", "type": "Agent" }, "contributionDate": { "date": "2026/4/16", "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/CA121420/MONDO:0018544/105/el/0/1648/1650", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA121420/MONDO:0018544/105/ci/CA121420/MONDO:0018544/105.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50049_EP177618055787822", "id": "CG-PCER-AGENT:CG_50049_EP177618055787822", "type": "Agent" }, "comments": "In Korenke GC et al. 1996 (PMID: 8773611), the twins' mother , maternal aunt, and grandmother all showed mild symptoms of AMN with disturbances of sensibility and reduced vibration sense. The same mutation of the probands (twin boys with AMN) was found at the heterozygous state. \n\nAdditional co-segregations from other reports that count toward PP1:\n- In Coll MJ et al. 2005 (PMID: 15811009) two affected members of the same family have the same variant. \n- In Kok F et al. 1995 (PMID: 7581394) one kindred is reported with S606L and Addison's phenotype in addition to the index case (#21, see table 2).", "contributionDate": { "date": "2026/4/16", "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": "CA121420/MONDO:0018544/105/ci/CA121420/MONDO:0018544/105.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA121420/MONDO:0018544/105/0/1648/1650", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA121420/MONDO:0018544/105/1/1649", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA121420/MONDO:0018544/105/0/1648", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA121420/MONDO:0018544/105/el/0/1696", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA121420/MONDO:0018544/105/ei/1/1697", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50049_EP177618055787822", "id": "CG-PCER-AGENT:CG_50049_EP177618055787822", "type": "Agent" }, "contributionDate": { "date": "2026/4/16", "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/CA121420/MONDO:0018544/105/el/0/1696/1698", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA121420/MONDO:0018544/105/ci/CA121420/MONDO:0018544/105.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50049_EP177618055787822", "id": "CG-PCER-AGENT:CG_50049_EP177618055787822", "type": "Agent" }, "comments": "p.Ser606Leu showed significantly lower expression than wild type, was degraded by proteasomes after dimerization and beta-oxidation activity was not restored. Protein was correctly localized to peroxisomes. It is hypothesized that this variant affects the stability of the protein.\nSupporting level is selected as there is a reduction in expression in protein levels. Although B-oxidation activity was markedly reduced compared to mock, moderate strength cannot be selected as the reduction is not below <26% activity of WT (see Fig.3 in Takahashi N.) per specification.\n", "contributionDate": { "date": "2026/4/16", "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": "CA121420/MONDO:0018544/105/ci/CA121420/MONDO:0018544/105.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA121420/MONDO:0018544/105/0/1696/1698", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA121420/MONDO:0018544/105/1/1697", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA121420/MONDO:0018544/105/0/1696", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA121420/MONDO:0018544/105/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA121420/MONDO:0018544/105/ei/1/1748", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50049_EP177618055787822", "id": "CG-PCER-AGENT:CG_50049_EP177618055787822", "type": "Agent" }, "contributionDate": { "date": "2026/4/16", "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/CA121420/MONDO:0018544/105/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA121420/MONDO:0018544/105/ci/CA121420/MONDO:0018544/105.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50049_EP177618055787822", "id": "CG-PCER-AGENT:CG_50049_EP177618055787822", "type": "Agent" }, "comments": "p.Ser606Leu has a REVEL score of 0.935 which is above the cut-off of 0.85 for pathogenicity at the supporting level, thus PP3_supporting.", "contributionDate": { "date": "2026/4/16", "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": "CA121420/MONDO:0018544/105/ci/CA121420/MONDO:0018544/105.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA121420/MONDO:0018544/105/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA121420/MONDO:0018544/105/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA121420/MONDO:0018544/105/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA121420/MONDO:0018544/105/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA121420/MONDO:0018544/105/ei/1/1637", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50049_EP177618055787822", "id": "CG-PCER-AGENT:CG_50049_EP177618055787822", "type": "Agent" }, "contributionDate": { "date": "2026/4/16", "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/CA121420/MONDO:0018544/105/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA121420/MONDO:0018544/105/ci/CA121420/MONDO:0018544/105.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50049_EP177618055787822", "id": "CG-PCER-AGENT:CG_50049_EP177618055787822", "type": "Agent" }, "comments": "p.Ser606Leu is absent in males in gnomad v2.1 and v3.1. One heterozygous female is present in EUR population in both gnomad versions. it is absent in v4", "contributionDate": { "date": "2026/4/16", "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": "CA121420/MONDO:0018544/105/ci/CA121420/MONDO:0018544/105.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA121420/MONDO:0018544/105/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA121420/MONDO:0018544/105/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA121420/MONDO:0018544/105/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA121420/MONDO:0018544/105/el/0/1831", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA121420/MONDO:0018544/105/ei/1/1832", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50049_EP177618055787822", "id": "CG-PCER-AGENT:CG_50049_EP177618055787822", "type": "Agent" }, "contributionDate": { "date": "2026/4/16", "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/CA121420/MONDO:0018544/105/el/0/1831/1833", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA121420/MONDO:0018544/105/ci/CA121420/MONDO:0018544/105.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50049_EP177618055787822", "id": "CG-PCER-AGENT:CG_50049_EP177618055787822", "type": "Agent" }, "comments": "p.Ser606Leu is currently identified in 43 ALD cases based on the ALD database. We select and apply PP4_Moderate to a case from Korenke et al. (1996). Based on the specification table we selected evidence A + D + F, thus PP4_Moderate. ", "contributionDate": { "date": "2026/4/16", "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": "CA121420/MONDO:0018544/105/ci/CA121420/MONDO:0018544/105.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA121420/MONDO:0018544/105/0/1831/1833", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA121420/MONDO:0018544/105/1/1832", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA121420/MONDO:0018544/105/0/1831", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA121420/MONDO:0018544/105/el/0/1615", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA121420/MONDO:0018544/105/ei/1/1616", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50049_EP177618055787822", "id": "CG-PCER-AGENT:CG_50049_EP177618055787822", "type": "Agent" }, "contributionDate": { "date": "2026/4/16", "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/CA121420/MONDO:0018544/105/el/0/1615/1617", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA121420/MONDO:0018544/105/ci/CA121420/MONDO:0018544/105.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50049_EP177618055787822", "id": "CG-PCER-AGENT:CG_50049_EP177618055787822", "type": "Agent" }, "comments": "p.Ser606Leu is just upstream of the Walker B domain (starting at 617 aa) which is a well-established mutational hot spot. According to current specifications the C-sequence is not considered a hot spot, however variants in the Walker B domain show functional evidence similar to those of p.Ser606Leu, thus suggesting that the functional impact of variants in the C-sequence may be similar to those in the Walker A, B domains.\n\n* to be discussed if C-sequence will need to be added as hot spot together with Walker A and B domains.", "contributionDate": { "date": "2026/4/16", "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": "CA121420/MONDO:0018544/105/ci/CA121420/MONDO:0018544/105.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA121420/MONDO:0018544/105/0/1615/1617", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA121420/MONDO:0018544/105/1/1616", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA121420/MONDO:0018544/105/0/1615", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA121420/MONDO:0018544/105/el/0/1780", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA121420/MONDO:0018544/105/ei/1/1781", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50049_EP177618055787822", "id": "CG-PCER-AGENT:CG_50049_EP177618055787822", "type": "Agent" }, "contributionDate": { "date": "2026/4/16", "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/CA121420/MONDO:0018544/105/el/0/1780/1782", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA121420/MONDO:0018544/105/ci/CA121420/MONDO:0018544/105.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50049_EP177618055787822", "id": "CG-PCER-AGENT:CG_50049_EP177618055787822", "type": "Agent" }, "comments": "this code could potentially be applied due to pathogenicity of c.1816T>C (p.Ser606Pro), however since this code is not needed to reach pathogenic status for this variant, it will not be applied.", "contributionDate": { "date": "2026/4/16", "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": "CA121420/MONDO:0018544/105/ci/CA121420/MONDO:0018544/105.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA121420/MONDO:0018544/105/0/1780/1782", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA121420/MONDO:0018544/105/1/1781", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA121420/MONDO:0018544/105/0/1780", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA121420/MONDO:0018544/105/el/0/1735", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA121420/MONDO:0018544/105/ei/1/1736", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50049_EP177618055787822", "id": "CG-PCER-AGENT:CG_50049_EP177618055787822", "type": "Agent" }, "contributionDate": { "date": "2026/4/16", "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/CA121420/MONDO:0018544/105/el/0/1735/1737", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA121420/MONDO:0018544/105/ci/CA121420/MONDO:0018544/105.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50049_EP177618055787822", "id": "CG-PCER-AGENT:CG_50049_EP177618055787822", "type": "Agent" }, "comments": "several cases reported meet PP4 criteria with at least supporting evidence level (A/B/C + F) as listed below. ", "contributionDate": { "date": "2026/4/16", "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": "CA121420/MONDO:0018544/105/ci/CA121420/MONDO:0018544/105.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA121420/MONDO:0018544/105/0/1735/1737", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA121420/MONDO:0018544/105/1/1736", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA121420/MONDO:0018544/105/0/1735", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA121420/MONDO:0018544/105", "metadata": { "created": "2026-04-16T19:49:46.678Z", "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": "Thu, 16 Apr 2026 19:49:46 -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": "a227d34e-93cb-4314-936d-5711bf74115f", "variant": { "@id": "https://reg.genome.network/allele/CA121420", "id": "CAR:CA121420", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000033.4:c.1817C>T" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000033.4(ABCD1):c.1817C>T (p.Ser606Leu)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-10-14T05:40:45.213Z" } }, "status": { "code": 200, "name": "OK" } }