{
  "data": {
    "@context": "https://erepo.genome.network/evrepo/api/context",
    "@id": "https://cgerepoapi/evrepo/api/summary/classification/5e6acb29-c2f8-443c-a4e2-a70d61308b32/doc/sepio/version/1.1.0",
    "assertionMethod": {
      "@id": "https://cspec.genome.network/cspec/SequenceVariantInterpretation/id/1566365955",
      "label": "ClinGen Leber Congenital Amaurosis/early onset Retinal Dystrophy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPE65 Version 1.0",
      "type": "VariantPathogenicityInterpretationGuideline",
      "version": "1.0"
    },
    "condition": {
      "@id": "https://api.monarchinitiative.org/api/bioentity/phenotype/MONDO:0100368",
      "id": "MONDO:0100368",
      "label": "RPE65-related recessive retinopathy",
      "type": "GeneticCondition"
    },
    "evidenceLine": [
      {
        "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226550/MONDO:0100368/120/el/0/1690",
        "evidenceItem": [
          {
            "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226550/MONDO:0100368/120/ei/1/1691",
            "contribution": [
              {
                "agent": {
                  "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50082_EP170326324571166",
                  "id": "CG-PCER-AGENT:CG_50082_EP170326324571166",
                  "type": "Agent"
                },
                "contributionDate": {
                  "date": "2026/9/22",
                  "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/0025",
              "defaultStrength": {
                "@id": "https://obofoundry.org/sepio/SEPIO:0000216",
                "id": "SEPIO:0000216",
                "label": "Pathogenic Moderate"
              },
              "id": "0025",
              "label": "PP3",
              "type": "Criterion"
            },
            "evidenceLine": [
              {
                "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226550/MONDO:0100368/120/el/0/1690/1692",
                "evidenceItem": [
                  {
                    "@id": "CG-PCER:curatorInference/CA226550/MONDO:0100368/120/ci/CA226550/MONDO:0100368/120.002",
                    "contribution": [
                      {
                        "agent": {
                          "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50082_EP170326324571166",
                          "id": "CG-PCER-AGENT:CG_50082_EP170326324571166",
                          "type": "Agent"
                        },
                        "comments": "The computational predictor REVEL gives a score of 0.977, which is above the ClinGen LCA / eoRD VCEP threshold of ≥ 0.773 and predicts a damaging effect on RPE65 function (PP3_Moderate).",
                        "contributionDate": {
                          "date": "2026/9/22",
                          "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": "CA226550/MONDO:0100368/120/ci/CA226550/MONDO:0100368/120.002",
                    "type": "InfFromBkgrndSciKnow"
                  }
                ],
                "id": "CG-PCER-VARINT:CA226550/MONDO:0100368/120/0/1690/1692",
                "type": "EvidenceLine"
              }
            ],
            "id": "CG-PCER-VARINT:CA226550/MONDO:0100368/120/1/1691",
            "statementOutcome": {
              "@id": "SEPIO:0000224",
              "label": "Met"
            },
            "type": "CriterionAssessment"
          }
        ],
        "evidenceStrength": {
          "@id": "https://obofoundry.org/sepio"
        },
        "id": "CG-PCER-VARINT:CA226550/MONDO:0100368/120/0/1690",
        "type": "EvidenceLine"
      },
      {
        "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226550/MONDO:0100368/120/el/0/1696",
        "evidenceItem": [
          {
            "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226550/MONDO:0100368/120/ei/1/1697",
            "contribution": [
              {
                "agent": {
                  "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50082_EP170326324571166",
                  "id": "CG-PCER-AGENT:CG_50082_EP170326324571166",
                  "type": "Agent"
                },
                "contributionDate": {
                  "date": "2026/9/22",
                  "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/0045",
              "defaultStrength": {
                "@id": "https://obofoundry.org/sepio/SEPIO:0000329",
                "id": "SEPIO:0000329",
                "label": "Pathogenic Supporting"
              },
              "id": "0045",
              "label": "PS3",
              "type": "Criterion"
            },
            "evidenceLine": [
              {
                "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226550/MONDO:0100368/120/el/0/1696/1698",
                "evidenceItem": [
                  {
                    "@id": "CG-PCER:curatorInference/CA226550/MONDO:0100368/120/ci/CA226550/MONDO:0100368/120.002",
                    "contribution": [
                      {
                        "agent": {
                          "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50082_EP170326324571166",
                          "id": "CG-PCER-AGENT:CG_50082_EP170326324571166",
                          "type": "Agent"
                        },
                        "comments": "The variant exhibited no detectable enzymatic activity in a retinoid isomerase assay relative to the wild-type control, which is lower than the ClinGen LCA / eoRD VCEP PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function (PMID: 16828753, PS3_Supporting).",
                        "contributionDate": {
                          "date": "2026/9/22",
                          "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": "CA226550/MONDO:0100368/120/ci/CA226550/MONDO:0100368/120.002",
                    "type": "InfFromBkgrndSciKnow"
                  }
                ],
                "id": "CG-PCER-VARINT:CA226550/MONDO:0100368/120/0/1696/1698",
                "type": "EvidenceLine"
              }
            ],
            "id": "CG-PCER-VARINT:CA226550/MONDO:0100368/120/1/1697",
            "statementOutcome": {
              "@id": "SEPIO:0000224",
              "label": "Met"
            },
            "type": "CriterionAssessment"
          }
        ],
        "evidenceStrength": {
          "@id": "https://obofoundry.org/sepio"
        },
        "id": "CG-PCER-VARINT:CA226550/MONDO:0100368/120/0/1696",
        "type": "EvidenceLine"
      },
      {
        "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226550/MONDO:0100368/120/el/0/1633",
        "evidenceItem": [
          {
            "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226550/MONDO:0100368/120/ei/1/1634",
            "contribution": [
              {
                "agent": {
                  "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50082_EP170326324571166",
                  "id": "CG-PCER-AGENT:CG_50082_EP170326324571166",
                  "type": "Agent"
                },
                "contributionDate": {
                  "date": "2026/9/22",
                  "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/0063",
              "defaultStrength": {
                "@id": "https://obofoundry.org/sepio/SEPIO:0000329",
                "id": "SEPIO:0000329",
                "label": "Pathogenic Supporting"
              },
              "id": "0063",
              "label": "PP4",
              "type": "Criterion"
            },
            "evidenceLine": [
              {
                "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226550/MONDO:0100368/120/el/0/1633/1635",
                "evidenceItem": [
                  {
                    "@id": "CG-PCER:curatorInference/CA226550/MONDO:0100368/120/ci/CA226550/MONDO:0100368/120.002",
                    "contribution": [
                      {
                        "agent": {
                          "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50082_EP170326324571166",
                          "id": "CG-PCER-AGENT:CG_50082_EP170326324571166",
                          "type": "Agent"
                        },
                        "comments": "At least one proband harboring this variant exhibits a phenotype including diagnosis of Leber congenital amaurosis (0.5 pts), reduced visual acuity (1 pt), macular atrophic changes (0.5 pts), abnormal ERG, visual field constriction (1 pt), vessel attenuation (0.5 pts), and RPE depigmentation and granularity in the fundus (0.5 pts), which together are specific for RPE65-related recessive retinopathy (total 4 pts, PMID: 19117922, PP4).",
                        "contributionDate": {
                          "date": "2026/9/22",
                          "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": "CA226550/MONDO:0100368/120/ci/CA226550/MONDO:0100368/120.002",
                    "type": "InfFromBkgrndSciKnow"
                  }
                ],
                "id": "CG-PCER-VARINT:CA226550/MONDO:0100368/120/0/1633/1635",
                "type": "EvidenceLine"
              }
            ],
            "id": "CG-PCER-VARINT:CA226550/MONDO:0100368/120/1/1634",
            "statementOutcome": {
              "@id": "SEPIO:0000224",
              "label": "Met"
            },
            "type": "CriterionAssessment"
          }
        ],
        "evidenceStrength": {
          "@id": "https://obofoundry.org/sepio"
        },
        "id": "CG-PCER-VARINT:CA226550/MONDO:0100368/120/0/1633",
        "type": "EvidenceLine"
      },
      {
        "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226550/MONDO:0100368/120/el/0/1636",
        "evidenceItem": [
          {
            "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226550/MONDO:0100368/120/ei/1/1637",
            "contribution": [
              {
                "agent": {
                  "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50082_EP170326324571166",
                  "id": "CG-PCER-AGENT:CG_50082_EP170326324571166",
                  "type": "Agent"
                },
                "contributionDate": {
                  "date": "2026/9/22",
                  "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/CA226550/MONDO:0100368/120/el/0/1636/1638",
                "evidenceItem": [
                  {
                    "@id": "CG-PCER:curatorInference/CA226550/MONDO:0100368/120/ci/CA226550/MONDO:0100368/120.002",
                    "contribution": [
                      {
                        "agent": {
                          "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50082_EP170326324571166",
                          "id": "CG-PCER-AGENT:CG_50082_EP170326324571166",
                          "type": "Agent"
                        },
                        "comments": "This variant is present in gnomAD v.4.1.1 at a GrpMax allele frequency of 2.800e-7, with 2 alleles / 1180024 total alleles in the European (non-Finnish) population, which is lower than the ClinGen LCA / eoRD VCEP PM2_Supporting threshold of <0.0002 (PM2_Supporting).",
                        "contributionDate": {
                          "date": "2026/9/22",
                          "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": "CA226550/MONDO:0100368/120/ci/CA226550/MONDO:0100368/120.002",
                    "type": "InfFromBkgrndSciKnow"
                  }
                ],
                "id": "CG-PCER-VARINT:CA226550/MONDO:0100368/120/0/1636/1638",
                "type": "EvidenceLine"
              }
            ],
            "id": "CG-PCER-VARINT:CA226550/MONDO:0100368/120/1/1637",
            "statementOutcome": {
              "@id": "SEPIO:0000224",
              "label": "Met"
            },
            "type": "CriterionAssessment"
          }
        ],
        "evidenceStrength": {
          "@id": "https://obofoundry.org/sepio"
        },
        "id": "CG-PCER-VARINT:CA226550/MONDO:0100368/120/0/1636",
        "type": "EvidenceLine"
      },
      {
        "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226550/MONDO:0100368/120/el/0/1717",
        "evidenceItem": [
          {
            "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226550/MONDO:0100368/120/ei/1/1718",
            "contribution": [
              {
                "agent": {
                  "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50082_EP170326324571166",
                  "id": "CG-PCER-AGENT:CG_50082_EP170326324571166",
                  "type": "Agent"
                },
                "contributionDate": {
                  "date": "2026/9/22",
                  "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/007",
              "defaultStrength": {
                "@id": "https://obofoundry.org/sepio/SEPIO:0000216",
                "id": "SEPIO:0000216",
                "label": "Pathogenic Moderate"
              },
              "id": "007",
              "label": "PM3",
              "type": "Criterion"
            },
            "evidenceLine": [
              {
                "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA226550/MONDO:0100368/120/el/0/1717/1719",
                "evidenceItem": [
                  {
                    "@id": "CG-PCER:curatorInference/CA226550/MONDO:0100368/120/ci/CA226550/MONDO:0100368/120.002",
                    "contribution": [
                      {
                        "agent": {
                          "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50082_EP170326324571166",
                          "id": "CG-PCER-AGENT:CG_50082_EP170326324571166",
                          "type": "Agent"
                        },
                        "comments": "This variant has been reported in at least 2 apparently unrelated probands with early-onset severe retinal dystrophy who were homozygous for the variant (1 pt, PMID: 19117922, PMID: 11462243, PMID: 28127548, PM3).",
                        "contributionDate": {
                          "date": "2026/9/22",
                          "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": "CA226550/MONDO:0100368/120/ci/CA226550/MONDO:0100368/120.002",
                    "type": "InfFromBkgrndSciKnow"
                  }
                ],
                "id": "CG-PCER-VARINT:CA226550/MONDO:0100368/120/0/1717/1719",
                "type": "EvidenceLine"
              }
            ],
            "id": "CG-PCER-VARINT:CA226550/MONDO:0100368/120/1/1718",
            "statementOutcome": {
              "@id": "SEPIO:0000224",
              "label": "Met"
            },
            "type": "CriterionAssessment"
          }
        ],
        "evidenceStrength": {
          "@id": "https://obofoundry.org/sepio"
        },
        "id": "CG-PCER-VARINT:CA226550/MONDO:0100368/120/0/1717",
        "type": "EvidenceLine"
      }
    ],
    "id": "CG-PCER-VARINT:CA226550/MONDO:0100368/120",
    "metadata": {
      "created": "2026-10-15T19:02:09.079Z",
      "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, 15 Oct 2026 19:02:08 -0000",
      "schemaLabel": "Evidence Repository.Beta-1 (Unofficial)",
      "version": "1.1.0"
    },
    "statementOutcome": {
      "@id": "https://loinc.org/LA26332-9",
      "id": "LN:LA26332-9",
      "label": "Likely Pathogenic"
    },
    "type": "VariantPathogenicityInterpretation",
    "uuid": "5e6acb29-c2f8-443c-a4e2-a70d61308b32",
    "variant": {
      "@id": "https://reg.genome.network/allele/CA226550",
      "id": "CAR:CA226550",
      "relatedContextualAllele": [
        {
          "alleleName": [
            {
              "name": "NM_000329.3:c.430T>G"
            }
          ],
          "preferred": true
        }
      ],
      "relatedIdentifier": [
        {
          "label": "NM_000329.3(RPE65):c.430T>G (p.Tyr144Asp)"
        }
      ],
      "type": "CAR"
    }
  },
  "metadata": {
    "rendered": {
      "by": "https://erepo.genome.network/evrepo/api/summary/srvc",
      "when": "2026-11-05T02:24:20.491Z"
    }
  },
  "status": {
    "code": 200,
    "name": "OK"
  }
}