{
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    "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 1.1.0",
      "type": "VariantPathogenicityInterpretationGuideline",
      "version": "1.1.0"
    },
    "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/CA402994533/MONDO:0012999/026/el/0/1651",
        "evidenceItem": [
          {
            "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA402994533/MONDO:0012999/026/ei/1/1652",
            "contribution": [
              {
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                  "id": "CG-PCER-AGENT:CG_50047_EP16649150327501",
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                "contributionDate": {
                  "date": "2024/6/24",
                  "description": "Date on which this evidence was provided"
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                "contributionRole": {
                  "@id": "https://obofoundry.org/sepio/0000156",
                  "id": "SEPIO:0000516",
                  "label": "curator role",
                  "type": "ContributoryRole"
                },
                "type": "Contribution"
              }
            ],
            "criterion": {
              "@id": "https://obofoundry.org/sepio/clingen/0058",
              "defaultStrength": {
                "@id": "https://obofoundry.org/sepio/SEPIO:0000330",
                "id": "SEPIO:0000330",
                "label": "Pathogenic Strong"
              },
              "id": "0058",
              "label": "PM3",
              "type": "Criterion"
            },
            "evidenceLine": [
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                          "type": "Agent"
                        },
                        "comments": "This variant was detected in three individuals with GAMT deficiency (PMID: 23660394, PMID: 24268530). These individuals are all compound heterozygous for the variant and another variant in GAMT that has been classified as pathogenic by the ClinGen CCDS VCEP including c.522G>A (p.Trp174Ter) (ClinVar Variation ID: 205584, SCV002600143.1), confirmed in trans by parental testing (PMID: 23660394, PMID: 24268530) (1 point), c.299_311dup (ClinVar Variation ID: 8302, SCV002600154.1) confirmed in trans by parental testing (Association for Creatine Deficiencies registry) (1 point), and c.59G>C (p.Trp20Ser) (ClinVar Variation ID: 8303, SCV004009593.1), phase unconfirmed (Association for Creatine Deficiencies registry) 0.5 points). Total 2.5 points (PM3_Strong)",
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                "type": "EvidenceLine"
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            ],
            "id": "CG-PCER-VARINT:CA402994533/MONDO:0012999/026/1/1652",
            "statementOutcome": {
              "@id": "SEPIO:0000224",
              "label": "Met"
            },
            "type": "CriterionAssessment"
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        ],
        "evidenceStrength": {
          "@id": "https://obofoundry.org/sepio"
        },
        "id": "CG-PCER-VARINT:CA402994533/MONDO:0012999/026/0/1651",
        "type": "EvidenceLine"
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      {
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        "evidenceItem": [
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            "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA402994533/MONDO:0012999/026/ei/1/1739",
            "contribution": [
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                "contributionDate": {
                  "date": "2024/6/24",
                  "description": "Date on which this evidence was provided"
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                "contributionRole": {
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                  "id": "SEPIO:0000516",
                  "label": "curator role",
                  "type": "ContributoryRole"
                },
                "type": "Contribution"
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            ],
            "criterion": {
              "@id": "https://obofoundry.org/sepio/clingen/005",
              "defaultStrength": {
                "@id": "https://obofoundry.org/sepio/SEPIO:0000330",
                "id": "SEPIO:0000330",
                "label": "Pathogenic Strong"
              },
              "id": "005",
              "label": "PP4",
              "type": "Criterion"
            },
            "evidenceLine": [
              {
                "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA402994533/MONDO:0012999/026/el/0/1738/1740",
                "evidenceItem": [
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                    "contribution": [
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                          "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50047_EP16649150327501",
                          "id": "CG-PCER-AGENT:CG_50047_EP16649150327501",
                          "type": "Agent"
                        },
                        "comments": "This variant has been identified in 3 individuals with a diagnosis of GAMT deficiency. One of these individuals had pretreatment marked elevation of guanidinoacetate and low/low normal creatine in plasma, urine, and CSF, and diminished creatine peak on brain MRS (ACD registry). Another proband  was reported with elevated guanidinoacetate in plasma (PMID: 23660394, PMID: 24268530) (PP4_Strong).",
                        "contributionDate": {
                          "date": "2024/6/24",
                          "description": "Date on which this evidence was provided"
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                          "@id": "https://obofoundry.org/sepio/0000156",
                          "id": "SEPIO:0000516",
                          "label": "curator role",
                          "type": "ContributoryRole"
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                        "type": "Contribution"
                      }
                    ],
                    "id": "CA402994533/MONDO:0012999/026/ci/CA402994533/MONDO:0012999/026.002",
                    "type": "InfFromBkgrndSciKnow"
                  }
                ],
                "id": "CG-PCER-VARINT:CA402994533/MONDO:0012999/026/0/1738/1740",
                "type": "EvidenceLine"
              }
            ],
            "id": "CG-PCER-VARINT:CA402994533/MONDO:0012999/026/1/1739",
            "statementOutcome": {
              "@id": "SEPIO:0000224",
              "label": "Met"
            },
            "type": "CriterionAssessment"
          }
        ],
        "evidenceStrength": {
          "@id": "https://obofoundry.org/sepio"
        },
        "id": "CG-PCER-VARINT:CA402994533/MONDO:0012999/026/0/1738",
        "type": "EvidenceLine"
      },
      {
        "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA402994533/MONDO:0012999/026/el/0/1774",
        "evidenceItem": [
          {
            "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA402994533/MONDO:0012999/026/ei/1/1775",
            "contribution": [
              {
                "agent": {
                  "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50047_EP16649150327501",
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                  "type": "Agent"
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                "contributionDate": {
                  "date": "2024/6/24",
                  "description": "Date on which this evidence was provided"
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                "contributionRole": {
                  "@id": "https://obofoundry.org/sepio/0000156",
                  "id": "SEPIO:0000516",
                  "label": "curator role",
                  "type": "ContributoryRole"
                },
                "type": "Contribution"
              }
            ],
            "criterion": {
              "@id": "https://obofoundry.org/sepio/clingen/0048",
              "defaultStrength": {
                "@id": "https://obofoundry.org/sepio/SEPIO:0000329",
                "id": "SEPIO:0000329",
                "label": "Pathogenic Supporting"
              },
              "id": "0048",
              "label": "PM5",
              "type": "Criterion"
            },
            "evidenceLine": [
              {
                "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA402994533/MONDO:0012999/026/el/0/1774/1776",
                "evidenceItem": [
                  {
                    "@id": "CG-PCER:curatorInference/CA402994533/MONDO:0012999/026/ci/CA402994533/MONDO:0012999/026.002",
                    "contribution": [
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                          "id": "CG-PCER-AGENT:CG_50047_EP16649150327501",
                          "type": "Agent"
                        },
                        "comments": "A different missense variant at the same codon, c.506G>A (p.Cys169Tyr) (ClinVar ID: 8304, SCV004009598.1),has been classified as likely pathogenic by the ClinGen CCDS VCEP.",
                        "contributionDate": {
                          "date": "2024/6/24",
                          "description": "Date on which this evidence was provided"
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                        "type": "Contribution"
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                    ],
                    "id": "CA402994533/MONDO:0012999/026/ci/CA402994533/MONDO:0012999/026.002",
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                  }
                ],
                "id": "CG-PCER-VARINT:CA402994533/MONDO:0012999/026/0/1774/1776",
                "type": "EvidenceLine"
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            ],
            "id": "CG-PCER-VARINT:CA402994533/MONDO:0012999/026/1/1775",
            "statementOutcome": {
              "@id": "SEPIO:0000224",
              "label": "Met"
            },
            "type": "CriterionAssessment"
          }
        ],
        "evidenceStrength": {
          "@id": "https://obofoundry.org/sepio"
        },
        "id": "CG-PCER-VARINT:CA402994533/MONDO:0012999/026/0/1774",
        "type": "EvidenceLine"
      },
      {
        "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA402994533/MONDO:0012999/026/el/0/1747",
        "evidenceItem": [
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            "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA402994533/MONDO:0012999/026/ei/1/1748",
            "contribution": [
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                  "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50047_EP16649150327501",
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                  "date": "2024/6/24",
                  "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/CA402994533/MONDO:0012999/026/el/0/1747/1749",
                "evidenceItem": [
                  {
                    "@id": "CG-PCER:curatorInference/CA402994533/MONDO:0012999/026/ci/CA402994533/MONDO:0012999/026.002",
                    "contribution": [
                      {
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                          "id": "CG-PCER-AGENT:CG_50047_EP16649150327501",
                          "type": "Agent"
                        },
                        "comments": "The computational predictor REVEL gives a score of 0.828, evidence that correlates with impact to GAMT function (PP3).",
                        "contributionDate": {
                          "date": "2024/6/24",
                          "description": "Date on which this evidence was provided"
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                        "type": "Contribution"
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                    ],
                    "id": "CA402994533/MONDO:0012999/026/ci/CA402994533/MONDO:0012999/026.002",
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                ],
                "id": "CG-PCER-VARINT:CA402994533/MONDO:0012999/026/0/1747/1749",
                "type": "EvidenceLine"
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            ],
            "id": "CG-PCER-VARINT:CA402994533/MONDO:0012999/026/1/1748",
            "statementOutcome": {
              "@id": "SEPIO:0000224",
              "label": "Met"
            },
            "type": "CriterionAssessment"
          }
        ],
        "evidenceStrength": {
          "@id": "https://obofoundry.org/sepio"
        },
        "id": "CG-PCER-VARINT:CA402994533/MONDO:0012999/026/0/1747",
        "type": "EvidenceLine"
      },
      {
        "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA402994533/MONDO:0012999/026/el/0/1636",
        "evidenceItem": [
          {
            "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA402994533/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": "2024/6/24",
                  "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/0030",
              "defaultStrength": {
                "@id": "https://obofoundry.org/sepio/SEPIO:0000329",
                "id": "SEPIO:0000329",
                "label": "Pathogenic Supporting"
              },
              "id": "0030",
              "label": "PM2",
              "type": "Criterion"
            },
            "evidenceLine": [
              {
                "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA402994533/MONDO:0012999/026/el/0/1636/1638",
                "evidenceItem": [
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                    "contribution": [
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                          "id": "CG-PCER-AGENT:CG_50047_EP16649150327501",
                          "type": "Agent"
                        },
                        "comments": "This variant is absent in gnomAD v2.1.1 (PM2_Supporting).",
                        "contributionDate": {
                          "date": "2024/6/24",
                          "description": "Date on which this evidence was provided"
                        },
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                          "@id": "https://obofoundry.org/sepio/0000156",
                          "id": "SEPIO:0000516",
                          "label": "curator role",
                          "type": "ContributoryRole"
                        },
                        "type": "Contribution"
                      }
                    ],
                    "id": "CA402994533/MONDO:0012999/026/ci/CA402994533/MONDO:0012999/026.002",
                    "type": "InfFromBkgrndSciKnow"
                  }
                ],
                "id": "CG-PCER-VARINT:CA402994533/MONDO:0012999/026/0/1636/1638",
                "type": "EvidenceLine"
              }
            ],
            "id": "CG-PCER-VARINT:CA402994533/MONDO:0012999/026/1/1637",
            "statementOutcome": {
              "@id": "SEPIO:0000224",
              "label": "Met"
            },
            "type": "CriterionAssessment"
          }
        ],
        "evidenceStrength": {
          "@id": "https://obofoundry.org/sepio"
        },
        "id": "CG-PCER-VARINT:CA402994533/MONDO:0012999/026/0/1636",
        "type": "EvidenceLine"
      }
    ],
    "id": "CG-PCER-VARINT:CA402994533/MONDO:0012999/026",
    "metadata": {
      "created": "2024-09-28T04:53:13.854Z",
      "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 04:53:13 -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": "f7d9b26e-41e5-47ec-846a-8e99d0e376f6",
    "variant": {
      "@id": "https://reg.genome.network/allele/CA402994533",
      "id": "CAR:CA402994533",
      "relatedContextualAllele": [
        {
          "alleleName": [
            {
              "name": "NM_000156.6:c.505T>C"
            }
          ],
          "preferred": true
        }
      ],
      "relatedIdentifier": [
        {
          "label": "NM_000156.6(GAMT):c.505T>C (p.Cys169Arg)"
        }
      ],
      "type": "CAR"
    }
  },
  "metadata": {
    "rendered": {
      "by": "https://erepo.genome.network/evrepo/api/summary/srvc",
      "when": "2026-10-29T02:18:03.763Z"
    }
  },
  "status": {
    "code": 200,
    "name": "OK"
  }
}