{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/5c72c382-0f01-44d1-aa6a-d90d93639061/doc/sepio/version/1.0.0", "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/CA9043637/MONDO:0012999/026/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA9043637/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/CA9043637/MONDO:0012999/026/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA9043637/MONDO:0012999/026/ci/CA9043637/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 highest population minor allele frequency in gnomAD v4.1.0. is 0.000015 (18/1180024 alleles) in the European non-Finnish population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting).\n", "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": "CA9043637/MONDO:0012999/026/ci/CA9043637/MONDO:0012999/026.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA9043637/MONDO:0012999/026/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA9043637/MONDO:0012999/026/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA9043637/MONDO:0012999/026/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA9043637/MONDO:0012999/026/el/0/1828", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA9043637/MONDO:0012999/026/ei/1/1829", "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/CA9043637/MONDO:0012999/026/el/0/1828/1830", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA9043637/MONDO:0012999/026/ci/EV000001938", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50047_EP16649150327501", "id": "CG-PCER-AGENT:CG_50047_EP16649150327501", "type": "Agent" }, "comments": "According to Table 2, when expressed in HeLa cells, the variant resulted in a significant decrease in enzyme activity (PS3_Supporting). (Possible typos, with variant as either c.467C>A, c.467C>G, p.Thr156Asp, p.Ala156Asp, and p.Ala156Arg)", "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": "CA9043637/MONDO:0012999/026/ci/EV000001938", "traceableAuthorStatement": "https://www.ncbi.nlm.nih.gov/pubmed/26003046", "type": "CuratorInference" } ], "id": "CG-PCER-VARINT:CA9043637/MONDO:0012999/026/0/1828/1830", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA9043637/MONDO:0012999/026/1/1829", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA9043637/MONDO:0012999/026/0/1828", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA9043637/MONDO:0012999/026/el/0/1690", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA9043637/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/CA9043637/MONDO:0012999/026/el/0/1690/1692", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA9043637/MONDO:0012999/026/ci/CA9043637/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 0.864 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). No impact on splicing is predicted by SpliceAI.", "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": "CA9043637/MONDO:0012999/026/ci/CA9043637/MONDO:0012999/026.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA9043637/MONDO:0012999/026/0/1690/1692", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA9043637/MONDO:0012999/026/1/1691", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA9043637/MONDO:0012999/026/0/1690", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA9043637/MONDO:0012999/026/el/0/1738", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA9043637/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/CA9043637/MONDO:0012999/026/el/0/1738/1740", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA9043637/MONDO:0012999/026/ci/CA9043637/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 individual with this variant (PMID: 40105081) had elevated GAA and low or low normal creatine in urine and significantly decreased creatine peak (GAA not reported) on brain MRS (4 points; 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": "CA9043637/MONDO:0012999/026/ci/CA9043637/MONDO:0012999/026.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA9043637/MONDO:0012999/026/0/1738/1740", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA9043637/MONDO:0012999/026/1/1739", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA9043637/MONDO:0012999/026/0/1738", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA9043637/MONDO:0012999/026/el/0/1717", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA9043637/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/CA9043637/MONDO:0012999/026/el/0/1717/1719", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA9043637/MONDO:0012999/026/ci/CA9043637/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 with features consistent with GAMT deficiency has been reported to be compound heterozygous for the variant and another variant in GAMT that has been classified as pathogenic for GAMT deficiency, c.194T>C (p.Leu65Pro); the variants were confirmed to be in trans by parents testing (Journal of Clinical Pediatrics, 2024 Vol.42 No.12 1039-1046 (article in Chinese), link to article - https://jcp.xinhuamed.com.cn/EN/10.12372/jcp.2024.24e0300). (1pt, 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": "CA9043637/MONDO:0012999/026/ci/CA9043637/MONDO:0012999/026.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA9043637/MONDO:0012999/026/0/1717/1719", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA9043637/MONDO:0012999/026/1/1718", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA9043637/MONDO:0012999/026/0/1717", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA9043637/MONDO:0012999/026", "metadata": { "created": "2025-12-10T20:14:37.155Z", "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 20:14:37 -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": "5c72c382-0f01-44d1-aa6a-d90d93639061", "variant": { "@id": "https://reg.genome.network/allele/CA9043637", "id": "CAR:CA9043637", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000156.6:c.467C>A" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000156.6(GAMT):c.467C>A (p.Ala156Asp)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-10-29T22:17:46.515Z" } }, "status": { "code": 200, "name": "OK" } }