{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/ddd3d58a-031d-4fb9-b992-a9be27c33545/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/CA402995480/MONDO:0012999/026/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA402995480/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/CA402995480/MONDO:0012999/026/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA402995480/MONDO:0012999/026/ci/CA402995480/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 0.0000223 (1/44874 alleles) in the East Asian population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (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": "CA402995480/MONDO:0012999/026/ci/CA402995480/MONDO:0012999/026.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA402995480/MONDO:0012999/026/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA402995480/MONDO:0012999/026/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA402995480/MONDO:0012999/026/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA402995480/MONDO:0012999/026/el/0/1828", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA402995480/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/CA402995480/MONDO:0012999/026/el/0/1828/1830", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA402995480/MONDO:0012999/026/ci/EV000001546", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50047_EP16649150327501", "id": "CG-PCER-AGENT:CG_50047_EP16649150327501", "type": "Agent" }, "comments": "Shown to result in abnormal splicing based on RT-PCR and cDNA analysis: ['One transcript had the complete exon 3 (64-bp) deletion by exon skipping and the other transcript was aberrantly spliced at exon 2 involving intron 2 insertion (44-bp) followed by exon 3 skipping, resulting in a 20-bp deletion. Both transcripts are expected to result in frame shift and premature termination of p.Val110Glyfs*30 and p.Ile111Profs*73, respectively.']", "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": "CA402995480/MONDO:0012999/026/ci/EV000001546", "traceableAuthorStatement": "https://www.ncbi.nlm.nih.gov/pubmed/23846910", "type": "CuratorInference" } ], "id": "CG-PCER-VARINT:CA402995480/MONDO:0012999/026/0/1828/1830", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA402995480/MONDO:0012999/026/1/1829", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA402995480/MONDO:0012999/026/0/1828", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA402995480/MONDO:0012999/026/el/0/1738", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA402995480/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/CA402995480/MONDO:0012999/026/el/0/1738/1740", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA402995480/MONDO:0012999/026/ci/CA402995480/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": "Patient reported showed absent creatine peak on brain magnetic resonance spectroscopy (3pts) and elevated urine guanidinoacetate with low creatine (1pt) with full GAMT gene sequencing (PP4_Strong, 4pts total) (PMID: 23846910). ", "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": "CA402995480/MONDO:0012999/026/ci/CA402995480/MONDO:0012999/026.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA402995480/MONDO:0012999/026/0/1738/1740", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA402995480/MONDO:0012999/026/1/1739", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA402995480/MONDO:0012999/026/0/1738", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA402995480/MONDO:0012999/026/el/0/1717", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA402995480/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/CA402995480/MONDO:0012999/026/el/0/1717/1719", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA402995480/MONDO:0012999/026/ci/CA402995480/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": "Reported in one patient (PMID: 23846910) who was a reported compound heterozygote and harbored a variant of uncertain significance (c.578A>G (p.Gln193Arg, ClinVar Variation ID: 1328978) in unknown phase. ", "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": "CA402995480/MONDO:0012999/026/ci/CA402995480/MONDO:0012999/026.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA402995480/MONDO:0012999/026/0/1717/1719", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA402995480/MONDO:0012999/026/1/1718", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA402995480/MONDO:0012999/026/0/1717", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA402995480/MONDO:0012999/026/el/0/1594", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA402995480/MONDO:0012999/026/ei/1/1595", "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/CA402995480/MONDO:0012999/026/el/0/1594/1596", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA402995480/MONDO:0012999/026/ci/CA402995480/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": "Shown to result in abnormal splicing, frameshift, and premature termination based on cDNA analysis from an affected individual (PMID: 23846910). Based on the chromatograms shown in the publication, the altered splicing seems incomplete; however, the report does not specify the percentage of alternately spliced transcript. Given the uncertainty about the degree of altered splicing, PVS1 was not applied. ", "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": "CA402995480/MONDO:0012999/026/ci/CA402995480/MONDO:0012999/026.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA402995480/MONDO:0012999/026/0/1594/1596", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA402995480/MONDO:0012999/026/1/1595", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA402995480/MONDO:0012999/026/0/1594", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA402995480/MONDO:0012999/026/el/0/1753", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA402995480/MONDO:0012999/026/ei/1/1754", "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/CA402995480/MONDO:0012999/026/el/0/1753/1755", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA402995480/MONDO:0012999/026/ci/CA402995480/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 NM_000156.6:c.391G>C variant in GAMT alters the last nucleotide of exon 3. The computational splicing predictor SpliceAI gives a score of 0.8 for donor loss, predicting that the variant disrupts the donor splice site of intron 3 of GAMT. If any protein is made, the variant is predicted to result in a missense, p.Gly131Arg. The computational predictor REVEL gives a score of 0.958 for this missense variant, which is above the threshold of 0.75, evidence that correlates with impact to GAMT function. ", "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": "CA402995480/MONDO:0012999/026/ci/CA402995480/MONDO:0012999/026.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA402995480/MONDO:0012999/026/0/1753/1755", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA402995480/MONDO:0012999/026/1/1754", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA402995480/MONDO:0012999/026/0/1753", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA402995480/MONDO:0012999/026", "metadata": { "created": "2025-12-10T20:39:17.916Z", "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 20:39:17 -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": "ddd3d58a-031d-4fb9-b992-a9be27c33545", "variant": { "@id": "https://reg.genome.network/allele/CA402995480", "id": "CAR:CA402995480", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_138924.3:c.391G>C" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_138924.3:c.391G>C" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-11-03T22:50:37.590Z" } }, "status": { "code": 200, "name": "OK" } }