{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/666f3a4c-7076-43ec-8c81-965928812a1e/doc/sepio/version/2.0.0", "assertionMethod": { "@id": "https://cspec.genome.network/cspec/SequenceVariantInterpretation/id/643243096", "label": "ClinGen Cerebral Creatine Deficiency Syndromes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GAMT Version 2.0.0", "type": "VariantPathogenicityInterpretationGuideline", "version": "2.0.0" }, "condition": { "@id": "https://api.monarchinitiative.org/api/bioentity/phenotype/MONDO:0012999", "id": "MONDO:0012999", "label": "guanidinoacetate methyltransferase deficiency", "type": "GeneticCondition" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA402998053/MONDO:0012999/026/el/0/1696", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA402998053/MONDO:0012999/026/ei/1/1697", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50047_EP16649150327501", "id": "CG-PCER-AGENT:CG_50047_EP16649150327501", "type": "Agent" }, "contributionDate": { "date": "2025/12/10", "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/CA402998053/MONDO:0012999/026/el/0/1696/1698", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA402998053/MONDO:0012999/026/ci/EV000001508", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50047_EP16649150327501", "id": "CG-PCER-AGENT:CG_50047_EP16649150327501", "type": "Agent" }, "comments": "When the variant was expressed in a primary GAMT-deficient human fibroblast cell line (homozygous for a frameshift mutation), no detectable expression could be seen on Western blot and the GAMT activity was very low (<4%).", "contributionDate": { "date": "2025/12/10", "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": "CA402998053/MONDO:0012999/026/ci/EV000001508", "traceableAuthorStatement": "https://www.ncbi.nlm.nih.gov/pubmed/24415674", "type": "CuratorInference" } ], "id": "CG-PCER-VARINT:CA402998053/MONDO:0012999/026/0/1696/1698", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA402998053/MONDO:0012999/026/1/1697", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA402998053/MONDO:0012999/026/0/1696", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA402998053/MONDO:0012999/026/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA402998053/MONDO:0012999/026/ei/1/1637", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50047_EP16649150327501", "id": "CG-PCER-AGENT:CG_50047_EP16649150327501", "type": "Agent" }, "contributionDate": { "date": "2025/12/10", "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/CA402998053/MONDO:0012999/026/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA402998053/MONDO:0012999/026/ci/CA402998053/MONDO:0012999/026.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50047_EP16649150327501", "id": "CG-PCER-AGENT:CG_50047_EP16649150327501", "type": "Agent" }, "comments": "This variant is absent in gnomAD v4.1.0. (PM2_Supporting).", "contributionDate": { "date": "2025/12/10", "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": "CA402998053/MONDO:0012999/026/ci/CA402998053/MONDO:0012999/026.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA402998053/MONDO:0012999/026/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA402998053/MONDO:0012999/026/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA402998053/MONDO:0012999/026/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA402998053/MONDO:0012999/026/el/0/1738", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA402998053/MONDO:0012999/026/ei/1/1739", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50047_EP16649150327501", "id": "CG-PCER-AGENT:CG_50047_EP16649150327501", "type": "Agent" }, "contributionDate": { "date": "2025/12/10", "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/CA402998053/MONDO:0012999/026/el/0/1738/1740", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA402998053/MONDO:0012999/026/ci/CA402998053/MONDO:0012999/026.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50047_EP16649150327501", "id": "CG-PCER-AGENT:CG_50047_EP16649150327501", "type": "Agent" }, "comments": "One proband has been reported with mild developmental delay, anti-epileptic drug responsive seizures, and autistic features, with a normal brain MRI. This individual had elevated guanidinoacetate in urine, 1.1-12 x normal (1 point), and on MRS, creatine peak was partially absent and guanidinoacetate peak was absent (3 points) (PMID: 15108290, 24415674) (PP4_Strong).", "contributionDate": { "date": "2025/12/10", "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": "CA402998053/MONDO:0012999/026/ci/CA402998053/MONDO:0012999/026.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA402998053/MONDO:0012999/026/0/1738/1740", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA402998053/MONDO:0012999/026/1/1739", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA402998053/MONDO:0012999/026/0/1738", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA402998053/MONDO:0012999/026/el/0/1717", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA402998053/MONDO:0012999/026/ei/1/1718", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50047_EP16649150327501", "id": "CG-PCER-AGENT:CG_50047_EP16649150327501", "type": "Agent" }, "contributionDate": { "date": "2025/12/10", "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/CA402998053/MONDO:0012999/026/el/0/1717/1719", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA402998053/MONDO:0012999/026/ci/CA402998053/MONDO:0012999/026.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50047_EP16649150327501", "id": "CG-PCER-AGENT:CG_50047_EP16649150327501", "type": "Agent" }, "comments": "One patient has been reported who is compound heterozygous for the variant and another variant in GAMT that has been classified as pathogenic for GAMT deficiency by the ClinGen CCDS VCEP; the variants were confirmed to be in trans (PMID: 15108290). 1 point, (PM3)", "contributionDate": { "date": "2025/12/10", "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": "CA402998053/MONDO:0012999/026/ci/CA402998053/MONDO:0012999/026.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA402998053/MONDO:0012999/026/0/1717/1719", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA402998053/MONDO:0012999/026/1/1718", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA402998053/MONDO:0012999/026/0/1717", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA402998053/MONDO:0012999/026/el/0/1690", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA402998053/MONDO:0012999/026/ei/1/1691", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50047_EP16649150327501", "id": "CG-PCER-AGENT:CG_50047_EP16649150327501", "type": "Agent" }, "contributionDate": { "date": "2025/12/10", "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/CA402998053/MONDO:0012999/026/el/0/1690/1692", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA402998053/MONDO:0012999/026/ci/CA402998053/MONDO:0012999/026.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50047_EP16649150327501", "id": "CG-PCER-AGENT:CG_50047_EP16649150327501", "type": "Agent" }, "comments": "The computational predictor REVEL gives a score of 0.814 which is in the range of 0.773-0.932, evidence that correlates with impact to GAMT function at the moderate level (PMID: 36413997) (PP3_Moderate).", "contributionDate": { "date": "2025/12/10", "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": "CA402998053/MONDO:0012999/026/ci/CA402998053/MONDO:0012999/026.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA402998053/MONDO:0012999/026/0/1690/1692", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA402998053/MONDO:0012999/026/1/1691", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA402998053/MONDO:0012999/026/0/1690", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA402998053/MONDO:0012999/026", "metadata": { "created": "2025-12-10T20:21:46.509Z", "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": "Wed, 10 Dec 2025 20:21:46 -0000", "schemaLabel": "Evidence Repository.Beta-1 (Unofficial)", "version": "2.0.0" }, "statementOutcome": { "@id": "https://loinc.org/LA6668-3", "id": "LN:LA6668-3", "label": "Pathogenic" }, "type": "VariantPathogenicityInterpretation", "uuid": "666f3a4c-7076-43ec-8c81-965928812a1e", "variant": { "@id": "https://reg.genome.network/allele/CA402998053", "id": "CAR:CA402998053", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_138924.3:c.152A>C" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_138924.3:c.152A>C" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-11-01T22:31:14.781Z" } }, "status": { "code": 200, "name": "OK" } }