{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/409ddea2-bc87-440b-9b4c-80f00c8b00ba/doc/sepio/version/1.0.0", "assertionMethod": { "@id": "https://cspec.genome.network/cspec/SequenceVariantInterpretation/id/485570930", "label": "ClinGen Leber Congenital Amaurosis/early onset Retinal Dystrophy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CEP290 Version 1.0", "type": "VariantPathogenicityInterpretationGuideline", "version": "1.0" }, "condition": { "@id": "https://api.monarchinitiative.org/api/bioentity/phenotype/MONDO:0100451", "id": "MONDO:0100451", "label": "CEP290-related ciliopathy", "type": "GeneticCondition" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6712876/MONDO:0100451/226/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6712876/MONDO:0100451/226/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": "2026/7/20", "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/CA6712876/MONDO:0100451/226/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA6712876/MONDO:0100451/226/ci/CA6712876/MONDO:0100451/226.002", "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 v4.1.1 at a total allele frequency of 0.00001501, with 24 alleles / 1.598.538 total alleles, which is lower than the ClinGen LCA/eoRD VCEP PM2_Supporting threshold of <0.0006 (PM2_Supporting).", "contributionDate": { "date": "2026/7/20", "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": "CA6712876/MONDO:0100451/226/ci/CA6712876/MONDO:0100451/226.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA6712876/MONDO:0100451/226/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA6712876/MONDO:0100451/226/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA6712876/MONDO:0100451/226/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6712876/MONDO:0100451/226/el/0/1684", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6712876/MONDO:0100451/226/ei/1/1685", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50082_EP170326324571166", "id": "CG-PCER-AGENT:CG_50082_EP170326324571166", "type": "Agent" }, "contributionDate": { "date": "2026/7/20", "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/CA6712876/MONDO:0100451/226/el/0/1684/1686", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA6712876/MONDO:0100451/226/ci/CA6712876/MONDO:0100451/226.002", "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 CADD gives a score of 23.8, which is above the ClinGen LCA/eoRD VCEP threshold of <17.3 and does not predict a non-damaging effect on CEP290 protein function. ", "contributionDate": { "date": "2026/7/20", "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": "CA6712876/MONDO:0100451/226/ci/CA6712876/MONDO:0100451/226.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA6712876/MONDO:0100451/226/0/1684/1686", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA6712876/MONDO:0100451/226/1/1685", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA6712876/MONDO:0100451/226/0/1684", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6712876/MONDO:0100451/226/el/0/1651", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6712876/MONDO:0100451/226/ei/1/1652", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50082_EP170326324571166", "id": "CG-PCER-AGENT:CG_50082_EP170326324571166", "type": "Agent" }, "contributionDate": { "date": "2026/7/20", "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/CA6712876/MONDO:0100451/226/el/0/1651/1653", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA6712876/MONDO:0100451/226/ci/CA6712876/MONDO:0100451/226.002", "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 1 proband with early-onset severe retinal dystrophy who was homozygous for the variant (0.5 points, PMID: 36909829). This variant has also been reported in at least 3 probands with early-onset severe retinal dystrophy who were compound heterozygous with either the NM_025114.4(CEP290):c.1984C>T (p.Gln662Ter) variant confirmed in trans (1 point, PMID: 34321860), the NM_025114.4(CEP290):c.1347dup (p.Asp450fs) variant confirmed in trans (1 point, VCEP member-provided data), or the NM_025114.4(CEP290):c.1753C>T (p.Gln585Ter) variant suspected in trans (0.5 points, VCEP member-provided data), which were previously classified pathogenic or likely pathogenic by the ClinGen LCA/eoRD VCEP (3 total points, PM3_Strong). This variant has been reported in two additional patients diagnosed with retinitis pigmentosa in adolescence or adulthood with no available details regarding onset with either the NM_025114.4(CEP290):c.254dup (p.Asn85fs) variant or the NM_025114.4(CEP290):c.1347dup (p.Asp450fs) variant suspected in trans. These have not been included in PM3 pending confirmation of necessary phenotype details.", "contributionDate": { "date": "2026/7/20", "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": "CA6712876/MONDO:0100451/226/ci/CA6712876/MONDO:0100451/226.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA6712876/MONDO:0100451/226/0/1651/1653", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA6712876/MONDO:0100451/226/1/1652", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA6712876/MONDO:0100451/226/0/1651", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6712876/MONDO:0100451/226/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6712876/MONDO:0100451/226/ei/1/1748", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50082_EP170326324571166", "id": "CG-PCER-AGENT:CG_50082_EP170326324571166", "type": "Agent" }, "contributionDate": { "date": "2026/7/20", "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/CA6712876/MONDO:0100451/226/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA6712876/MONDO:0100451/226/ci/CA6712876/MONDO:0100451/226.002", "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 CADD gives a score of 23.8, which is below the ClinGen LCA/eoRD VCEP threshold of ≥25.3 and does not predict a damaging effect on CEP290 protein function. Additionally, the splicing impact predictor SpliceAI gives a score of 0.0, which is below the ClinGen LCA/eoRD VCEP recommended threshold of ≥0.2 and does not strongly predict an impact on splicing.\n", "contributionDate": { "date": "2026/7/20", "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": "CA6712876/MONDO:0100451/226/ci/CA6712876/MONDO:0100451/226.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA6712876/MONDO:0100451/226/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA6712876/MONDO:0100451/226/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA6712876/MONDO:0100451/226/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6712876/MONDO:0100451/226/el/0/1633", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6712876/MONDO:0100451/226/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": "2026/7/20", "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/CA6712876/MONDO:0100451/226/el/0/1633/1635", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA6712876/MONDO:0100451/226/ci/CA6712876/MONDO:0100451/226.002", "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 retinitis pigmentosa with onset in infancy / childhood (0.5 pts), nyctalopia (0.5 pts), visual acuity 1.0/1.0, and moderate myopia, with genotyping by whole exome sequencing that did not identify an alternative basis for retinal disease (4 pts), which together are specific for CEP290-related ciliopathy (5 total points, PMID: 36909829, PP4).", "contributionDate": { "date": "2026/7/20", "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": "CA6712876/MONDO:0100451/226/ci/CA6712876/MONDO:0100451/226.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA6712876/MONDO:0100451/226/0/1633/1635", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA6712876/MONDO:0100451/226/1/1634", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA6712876/MONDO:0100451/226/0/1633", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA6712876/MONDO:0100451/226", "metadata": { "created": "2026-07-20T16:39:36.369Z", "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": "Mon, 20 Jul 2026 16:39:36 -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": "409ddea2-bc87-440b-9b4c-80f00c8b00ba", "variant": { "@id": "https://reg.genome.network/allele/CA6712876", "id": "CAR:CA6712876", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_025114.4:c.223A>G" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_025114.4(CEP290):c.223A>G (p.Lys75Glu)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-10-25T04:25:44.972Z" } }, "status": { "code": 200, "name": "OK" } }