{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/f8e77c54-95ee-4095-88d7-22c8e317f59f/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/CA6711895/MONDO:0100451/226/el/0/1597", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6711895/MONDO:0100451/226/ei/1/1598", "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/CA6711895/MONDO:0100451/226/el/0/1597/1599", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA6711895/MONDO:0100451/226/ci/CA6711895/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 a proband with early-onset severe retinal dystrophy in cis with the NM_025114.4(CEP290):c.-1G>A variant and in trans with the NM_025114.4(CEP290):c.3904C>T (p.Gln1302Ter) variant (PMID: 32165824). However, the variant in cis has not yet been classified by the ClinGen LCA/eoRD VCEP, so BP2 is not met.", "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": "CA6711895/MONDO:0100451/226/ci/CA6711895/MONDO:0100451/226.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA6711895/MONDO:0100451/226/0/1597/1599", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA6711895/MONDO:0100451/226/1/1598", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA6711895/MONDO:0100451/226/0/1597", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6711895/MONDO:0100451/226/el/0/1714", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6711895/MONDO:0100451/226/ei/1/1715", "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/CA6711895/MONDO:0100451/226/el/0/1714/1716", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA6711895/MONDO:0100451/226/ci/CA6711895/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 predicted to cause a change in the length of the protein due to an in-frame deletion encoding 1 amino acid in a non-repeat region, with at least one of the deleted base pairs highly conserved with a PhyloP conservation score of 7.37 (PM4_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": "CA6711895/MONDO:0100451/226/ci/CA6711895/MONDO:0100451/226.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA6711895/MONDO:0100451/226/0/1714/1716", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA6711895/MONDO:0100451/226/1/1715", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA6711895/MONDO:0100451/226/0/1714", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6711895/MONDO:0100451/226/el/0/1630", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6711895/MONDO:0100451/226/ei/1/1631", "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/CA6711895/MONDO:0100451/226/el/0/1630/1632", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA6711895/MONDO:0100451/226/ci/CA6711895/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 variant has been reported to segregate with childhood-onset severe retinal dystrophy through the proband plus 2 similarly affected relatives, with the variant present in the homozygous state (PP1_Moderate; PMID: 29398085).", "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": "CA6711895/MONDO:0100451/226/ci/CA6711895/MONDO:0100451/226.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA6711895/MONDO:0100451/226/0/1630/1632", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA6711895/MONDO:0100451/226/1/1631", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA6711895/MONDO:0100451/226/0/1630", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6711895/MONDO:0100451/226/el/0/1633", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6711895/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/CA6711895/MONDO:0100451/226/el/0/1633/1635", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA6711895/MONDO:0100451/226/ci/CA6711895/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 Leber congenital amaurosis (0.5 pts), onset before age 5 years (0.5 pts), extinguished electroretinogram responses from rods (0.5 pts) and cones (0.5 pts), central visual acuity limited to light perception (0.5 pts), white mottling in the peripheral pigmentation (0.5 pts), absence of vasculopathy / normal optic disc color, and decreased flash visual evoked potentials, with genotyping by next-generation sequencing identifying no alternative basis for retinal disease (2 pts), which together are specific for CEP290-related ciliopathy (total 5 points, PMID: 33970760, 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": "CA6711895/MONDO:0100451/226/ci/CA6711895/MONDO:0100451/226.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA6711895/MONDO:0100451/226/0/1633/1635", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA6711895/MONDO:0100451/226/1/1634", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA6711895/MONDO:0100451/226/0/1633", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6711895/MONDO:0100451/226/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6711895/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/CA6711895/MONDO:0100451/226/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA6711895/MONDO:0100451/226/ci/CA6711895/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 v.4.1.0 at a total allele frequency of 0.00002232, with 36 alleles / 1,612,700 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": "CA6711895/MONDO:0100451/226/ci/CA6711895/MONDO:0100451/226.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA6711895/MONDO:0100451/226/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA6711895/MONDO:0100451/226/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA6711895/MONDO:0100451/226/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6711895/MONDO:0100451/226/el/0/1669", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6711895/MONDO:0100451/226/ei/1/1670", "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/CA6711895/MONDO:0100451/226/el/0/1669/1671", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA6711895/MONDO:0100451/226/ci/CA6711895/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: 29398085). This variant has also been reported in at least 5 probands with early-onset severe retinal dystrophy who were compound heterozygous with the NM_025114.4(CEP290):c.4024C>T (p.Gln1342Ter) variant or the NM_025114.4(CEP290):c.5850del (p.Phe1950fs) variant suspected in trans (1 point, PMID: 33970760, PMID: 17345604) or with the NM_025114.4(CEP290):c.297+1G>T variant, the NM_025114.4(CEP290):c.3904C>T (p.Gln1302Ter) variant, or the NM_025114.4(CEP290):c.1219_1220del (p.Met407GlufsTer14) variant confirmed in trans (3 points, PMID: 28973549, PMID: 32165824, PMID: 34196655), which were previously classified pathogenic by the ClinGen LCA/eoRD VCEP (4.5 total points, PM3_VeryStrong).", "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": "CA6711895/MONDO:0100451/226/ci/CA6711895/MONDO:0100451/226.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA6711895/MONDO:0100451/226/0/1669/1671", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA6711895/MONDO:0100451/226/1/1670", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA6711895/MONDO:0100451/226/0/1669", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA6711895/MONDO:0100451/226", "metadata": { "created": "2026-07-20T19:33:17.379Z", "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 19:33:17 -0000", "schemaLabel": "Evidence Repository.Beta-1 (Unofficial)", "version": "1.0.0" }, "statementOutcome": { "@id": "https://loinc.org/LA6668-3", "id": "LN:LA6668-3", "label": "Pathogenic" }, "type": "VariantPathogenicityInterpretation", "uuid": "f8e77c54-95ee-4095-88d7-22c8e317f59f", "variant": { "@id": "https://reg.genome.network/allele/CA6711895", "id": "CAR:CA6711895", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_025114.4:c.4655AAG[2]" } ], "preferred": true }, { "alleleName": [ { "name": "NM_025114.4:c.4661_4663del" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_025114.4(CEP290):c.4655AAG[2] (p.Glu1554del)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-11-04T02:32:20.548Z" } }, "status": { "code": 200, "name": "OK" } }