{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://erepo.genome.network/evrepo/api/summary/classification/ea04729d-f891-485e-9f88-7aabaf604695/doc/sepio/version/1.0.0", "assertionMethod": { "@id": "https://cspec.genome.network/cspec/SequenceVariantInterpretation/id/643243140", "label": "ClinGen Epilepsy Sodium Channel Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SCN8A Version 2.0.0", "type": "VariantPathogenicityInterpretationGuideline", "version": "2.0.0" }, "condition": { "@id": "https://api.monarchinitiative.org/api/bioentity/phenotype/MONDO:0100038", "id": "MONDO:0100038", "label": "complex neurodevelopmental disorder", "type": "GeneticCondition" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA384880453/MONDO:0100038/070/el/0/1603", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA384880453/MONDO:0100038/070/ei/1/1604", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50105_EP171510966881719", "id": "CG-PCER-AGENT:CG_50105_EP171510966881719", "type": "Agent" }, "contributionDate": { "date": "2025/12/17", "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/CA384880453/MONDO:0100038/070/el/0/1603/1605", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA384880453/MONDO:0100038/070/ci/CA384880453/MONDO:0100038/070.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50105_EP171510966881719", "id": "CG-PCER-AGENT:CG_50105_EP171510966881719", "type": "Agent" }, "comments": "This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with Complex Neurodevelopmental Disorder in the Department of Genetics, Rouen University Hospital, France (PS2_Supporting; ClinVar Variation ID: 691254). Labcorp (Invitae) identified the variant in one individual with focal epilepsy in infancy, no familial testing was completed.", "contributionDate": { "date": "2025/12/17", "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": "CA384880453/MONDO:0100038/070/ci/CA384880453/MONDO:0100038/070.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA384880453/MONDO:0100038/070/0/1603/1605", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA384880453/MONDO:0100038/070/1/1604", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA384880453/MONDO:0100038/070/0/1603", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA384880453/MONDO:0100038/070/el/0/1774", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA384880453/MONDO:0100038/070/ei/1/1775", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50105_EP171510966881719", "id": "CG-PCER-AGENT:CG_50105_EP171510966881719", "type": "Agent" }, "contributionDate": { "date": "2025/12/17", "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/CA384880453/MONDO:0100038/070/el/0/1774/1776", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA384880453/MONDO:0100038/070/ci/CA384880453/MONDO:0100038/070.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50105_EP171510966881719", "id": "CG-PCER-AGENT:CG_50105_EP171510966881719", "type": "Agent" }, "comments": "NM_001330260.2(SCN8A):c.4893C>G (p.Ile1631Met)\nClinVar Variation ID: 3635210 (Submitted by Labcorp (formerly Invitae)\nClassified: LP (7 points)\n Met:\n PM2_Supporting: absent from gnomAD v4.1\n PP3_Moderate: REVEL 0.86 (0.773-0.932)\n PS2_Moderate: 2 points: 1 de novo case Complex Neurodevelopmental Disorder from GeneDx. It is published too at Supplementary Table 1, realated to de novo variants (ID - 94273 - Variant in GRCh37 (chr12-52200163 C>G)) from PMID: 33057194, 35982159). \n GeneDx specified: Male proband 42y at time of testing via trio exome, variant was de novo (confirmed). Phenotype: GTC seizures at 6mo, simple partial at 6y, auditory and visual hallucinations, mild ID, dolichocephaly, bitemporal narrowing, big ears, overweight.\n Labcorp (Invitae) has identified de variant as de novo with parentage confirmed in one individual with focal epilepsy in infancy.\n PS4_Moderate: GeneDx variant and Labcorp (Invitae) variant. 2 points\n \nNM_001330260.2(SCN8A):c.4892T>A (p.Ile1631Asn)\nClinVar Variation ID: 427167 (Submitted by GeneDx)\nClassified: VUS (3 points)\n Met:\n PM2_Supporting: absent from gnomAD v4.1\n PP3_Moderate: REVEL 0.98 (capped at Moderate)\n Not met:\n PM5: other VUS variants\n PM6: Unclear if de novo because only proband was tested. Female proband 6y at time of testing via an epilepsy panel of 53 genes (sequencing and del/dup analysis). Phenotype: Reported history of seizures and developmental delay\n\n***Paralogous Genes***\naa 1631 in SCN8A = 1640 in SCN2A\n\n*GeneDx\nSCN2A NM_021007 c.4919T>A (p.Ile1640Asn)\n2-months-old male at time of testing, trio exome, variant was de novo (confirmed)\nPhenotype of seizures, polymicrogyria, ventriculomegaly, jerks, apnea, bradycardia, colpocephaly, and concern for pituitary insufficiency.\nPM2_supporting, PP3_mod, PS2_supporting\n\n\nNM_001040142.2(SCN2A):c.4918A>C (p.Ile1640Leu)\nClinVar Variation ID: 2020237 (Submitted by Labcorp Genetics (formerly Invitae)\nClassified: VUS (3 points)\nMet:\nPM2_Supporting: absent from gnomAD v4.1\nPP3_Moderate: REVEL 0.8 (0.773-0.932)\nIt has been identified in one individual w/ history consistent with BFNIS. No segregation\n\n\nNM_001040142.2(SCN2A):c.4918A>T (p.Ile1640Phe)\nClinVar Variation ID: 835364 - Submitted by Labcorp and CENTOGENE\nClassified: LP (6 points)\nMet:\n PM2_Supporting: absent from gnomAD v4.1\n PP3_Moderate: REVEL 0.8 (0.773-0.932)\n PS2_supporting PMID: 30619928 Table 2 and 32712949 table S2 variant reported but without segregation. ClinVar says it is de novo but there is no supporting data\nLabcorp Genetics (formerly Invitae) identified the variant as de novo (with parentage confirmed) in individual w/ neonatal seizures.\n PS4_Moderate: 2 points. both patients by both submitters. Developmental and epileptic encephalopathy\n\n\n \n\n\n", "contributionDate": { "date": "2025/12/17", "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": "CA384880453/MONDO:0100038/070/ci/CA384880453/MONDO:0100038/070.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA384880453/MONDO:0100038/070/0/1774/1776", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA384880453/MONDO:0100038/070/1/1775", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA384880453/MONDO:0100038/070/0/1774", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA384880453/MONDO:0100038/070/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA384880453/MONDO:0100038/070/ei/1/1637", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50105_EP171510966881719", "id": "CG-PCER-AGENT:CG_50105_EP171510966881719", "type": "Agent" }, "contributionDate": { "date": "2025/12/17", "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/CA384880453/MONDO:0100038/070/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA384880453/MONDO:0100038/070/ci/CA384880453/MONDO:0100038/070.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50105_EP171510966881719", "id": "CG-PCER-AGENT:CG_50105_EP171510966881719", "type": "Agent" }, "comments": "This variant is absent from gnomAD v4.1 (PM2_Supporting).", "contributionDate": { "date": "2025/12/17", "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": "CA384880453/MONDO:0100038/070/ci/CA384880453/MONDO:0100038/070.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA384880453/MONDO:0100038/070/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA384880453/MONDO:0100038/070/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA384880453/MONDO:0100038/070/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA384880453/MONDO:0100038/070/el/0/1765", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA384880453/MONDO:0100038/070/ei/1/1766", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50105_EP171510966881719", "id": "CG-PCER-AGENT:CG_50105_EP171510966881719", "type": "Agent" }, "contributionDate": { "date": "2025/12/17", "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/CA384880453/MONDO:0100038/070/el/0/1765/1767", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA384880453/MONDO:0100038/070/ci/CA384880453/MONDO:0100038/070.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50105_EP171510966881719", "id": "CG-PCER-AGENT:CG_50105_EP171510966881719", "type": "Agent" }, "comments": "No Same amino acid change as a previously established pathogenic variant regardless of nucleotide\nNo identical Pathogenic and Likely Pathogenic variants in SCN1A, SCN2A, SCN3A", "contributionDate": { "date": "2025/12/17", "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": "CA384880453/MONDO:0100038/070/ci/CA384880453/MONDO:0100038/070.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA384880453/MONDO:0100038/070/0/1765/1767", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA384880453/MONDO:0100038/070/1/1766", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA384880453/MONDO:0100038/070/0/1765", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA384880453/MONDO:0100038/070/el/0/1699", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA384880453/MONDO:0100038/070/ei/1/1700", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50105_EP171510966881719", "id": "CG-PCER-AGENT:CG_50105_EP171510966881719", "type": "Agent" }, "contributionDate": { "date": "2025/12/17", "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/CA384880453/MONDO:0100038/070/el/0/1699/1701", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA384880453/MONDO:0100038/070/ci/CA384880453/MONDO:0100038/070.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50105_EP171510966881719", "id": "CG-PCER-AGENT:CG_50105_EP171510966881719", "type": "Agent" }, "comments": "Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.\n\nPatient from Labcorp Genetics (formerly Invitae) with focal epilepsy in infancy\nPatient fron Department of Genetics, Rouen University Hospital, France with Intellectual disability, Seizure, Autism", "contributionDate": { "date": "2025/12/17", "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": "CA384880453/MONDO:0100038/070/ci/CA384880453/MONDO:0100038/070.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA384880453/MONDO:0100038/070/0/1699/1701", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA384880453/MONDO:0100038/070/1/1700", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA384880453/MONDO:0100038/070/0/1699", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA384880453/MONDO:0100038/070/el/0/1690", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA384880453/MONDO:0100038/070/ei/1/1691", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50105_EP171510966881719", "id": "CG-PCER-AGENT:CG_50105_EP171510966881719", "type": "Agent" }, "contributionDate": { "date": "2025/12/17", "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/CA384880453/MONDO:0100038/070/el/0/1690/1692", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA384880453/MONDO:0100038/070/ci/CA384880453/MONDO:0100038/070.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50105_EP171510966881719", "id": "CG-PCER-AGENT:CG_50105_EP171510966881719", "type": "Agent" }, "comments": "The computational predictor REVEL gives a score of 0.98, which is higher than the threshold set >0.75 (PP3_Moderate). Although is ≥0.932 (Strong, PMID: 36413997) strength should be capped at Moderate.", "contributionDate": { "date": "2025/12/17", "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": "CA384880453/MONDO:0100038/070/ci/CA384880453/MONDO:0100038/070.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA384880453/MONDO:0100038/070/0/1690/1692", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA384880453/MONDO:0100038/070/1/1691", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA384880453/MONDO:0100038/070/0/1690", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA384880453/MONDO:0100038/070/el/0/1615", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA384880453/MONDO:0100038/070/ei/1/1616", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50105_EP171510966881719", "id": "CG-PCER-AGENT:CG_50105_EP171510966881719", "type": "Agent" }, "contributionDate": { "date": "2025/12/17", "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/CA384880453/MONDO:0100038/070/el/0/1615/1617", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA384880453/MONDO:0100038/070/ci/CA384880453/MONDO:0100038/070.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50105_EP171510966881719", "id": "CG-PCER-AGENT:CG_50105_EP171510966881719", "type": "Agent" }, "comments": "This variant does not reside within a region of SCN8A that is defined as a PER by the ClinGen Epilepsy Sodium Channel Expert Panel.", "contributionDate": { "date": "2025/12/17", "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": "CA384880453/MONDO:0100038/070/ci/CA384880453/MONDO:0100038/070.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA384880453/MONDO:0100038/070/0/1615/1617", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA384880453/MONDO:0100038/070/1/1616", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA384880453/MONDO:0100038/070/0/1615", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA384880453/MONDO:0100038/070", "metadata": { "created": "2025-12-17T18:01:37.666Z", "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, 17 Dec 2025 18:01:37 -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": "ea04729d-f891-485e-9f88-7aabaf604695", "variant": { "@id": "https://reg.genome.network/allele/CA384880453", "id": "CAR:CA384880453", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_001330260.2:c.4892T>C" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_001330260.2(SCN8A):c.4892T>C (p.Ile1631Thr)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-04-21T08:09:13.268Z" } }, "status": { "code": 200, "name": "OK" } }