{ "data": [ { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/be2941a7-23d4-4e6f-b888-bdfd4c496ba5/doc/sepio/version/1.0.0", "assertionMethod": { "@id": "https://cspec.genome.network/cspec/SequenceVariantInterpretation/id/135637582", "label": "ClinGen Lysosomal Storage Disorders Variant Curation Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2", "type": "VariantPathogenicityInterpretationGuideline", "url": "https://clinicalgenome.org/docs/clingen-lysosomal-storage-disorders-expert-panel-specifications-to-the-acmg-amp-variant-interpretation-guidelines-version-2/", "version": "2.0.0" }, "condition": { "@id": "https://api.monarchinitiative.org/api/bioentity/phenotype/MONDO:0009290", "id": "MONDO:0009290", "label": "glycogen storage disease II", "type": "GeneticCondition" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA116593/MONDO:0009290/010/el/0/1831", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA116593/MONDO:0009290/010/ei/1/1832", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50009_EP157972030954718", "id": "CG-PCER-AGENT:CG_50009_EP157972030954718", "type": "Agent" }, "contributionDate": { "date": "2024/12/17", "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/CA116593/MONDO:0009290/010/el/0/1831/1833", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA116593/MONDO:0009290/010/ci/CA116593/MONDO:0009290/010.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50009_EP157972030954718", "id": "CG-PCER-AGENT:CG_50009_EP157972030954718", "type": "Agent" }, "comments": "This variant was first reported in homozygosity in a case report of siblings with IOPD and no detectable GAA activity in fibroblasts (PMID: 1898413), meeting criteria for PP4_moderate. This variant has been detected in at least four additional individuals with IOPD (PMIDs: 17723315, 37542277, 19862843, 33301762). This variant has also been reported in at least nine individuals with LOPD. Of those, six were compound heterozygous for the common IVS splice site pathogenic variant c.-32-13T>G (PMIDs: 22676651, 20308911, 2270448, 20033296, 25673129, 30312517, 34852371 and 39045638). One was compound heterozygous for the variant and a pathogenic or likely pathogenic variant (PMID:21605996 and 22676651); one was compound heterozygous for a variant not previously reported, c.2161G>T (PMID: 25526786); and one was reported without a second variant documented (PMID: 10737124).", "contributionDate": { "date": "2024/12/17", "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": "CA116593/MONDO:0009290/010/ci/CA116593/MONDO:0009290/010.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA116593/MONDO:0009290/010/0/1831/1833", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA116593/MONDO:0009290/010/1/1832", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA116593/MONDO:0009290/010/0/1831", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA116593/MONDO:0009290/010/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA116593/MONDO:0009290/010/ei/1/1637", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50009_EP157972030954718", "id": "CG-PCER-AGENT:CG_50009_EP157972030954718", "type": "Agent" }, "contributionDate": { "date": "2024/12/17", "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/CA116593/MONDO:0009290/010/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA116593/MONDO:0009290/010/ci/CA116593/MONDO:0009290/010.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50009_EP157972030954718", "id": "CG-PCER-AGENT:CG_50009_EP157972030954718", "type": "Agent" }, "comments": "The highest population minor allele frequency in gnomAD v4.1.0. is 0.00003334 (2/59992 alleles) in the Admixed American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting).", "contributionDate": { "date": "2024/12/17", "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": "CA116593/MONDO:0009290/010/ci/CA116593/MONDO:0009290/010.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA116593/MONDO:0009290/010/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA116593/MONDO:0009290/010/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA116593/MONDO:0009290/010/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA116593/MONDO:0009290/010/el/0/1669", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA116593/MONDO:0009290/010/ei/1/1670", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50009_EP157972030954718", "id": "CG-PCER-AGENT:CG_50009_EP157972030954718", "type": "Agent" }, "contributionDate": { "date": "2024/12/17", "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/CA116593/MONDO:0009290/010/el/0/1669/1671", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA116593/MONDO:0009290/010/ci/CA116593/MONDO:0009290/010.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50009_EP157972030954718", "id": "CG-PCER-AGENT:CG_50009_EP157972030954718", "type": "Agent" }, "comments": "This variant has been detected in at least five individuals with IOPD. Of these, three were homozygous (PMIDs: 1898413,19862843, 33301762) and two were compound heterozygous for the variant and a pathogenic or likely pathogenic variant (c.2140del, PMID: 17723315 and c.1551+1G>A, PMID: 37542277). This variant has also been reported in at least nine individuals with LOPD. Of those, six were compound heterozygous for the common IVS splice site pathogenic variant c.-32-13T>G (PMIDs: 22676651, 20308911, 2270448, 20033296, 25673129, 30312517, 34852371 and 39045638). One was compound heterozygous for the variant and a pathogenic or likely pathogenic variant c.2297G>A (PMID: 21605996 and 22676651). Additionally, one was compound heterozygous for a variant not previously reported, c.2161G>T (PMID: 25526786); and one was reported without a second variant documented (PMID: 10737124).", "contributionDate": { "date": "2024/12/17", "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": "CA116593/MONDO:0009290/010/ci/CA116593/MONDO:0009290/010.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA116593/MONDO:0009290/010/0/1669/1671", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA116593/MONDO:0009290/010/1/1670", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA116593/MONDO:0009290/010/0/1669", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA116593/MONDO:0009290/010/el/0/1825", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA116593/MONDO:0009290/010/ei/1/1826", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50009_EP157972030954718", "id": "CG-PCER-AGENT:CG_50009_EP157972030954718", "type": "Agent" }, "contributionDate": { "date": "2024/12/17", "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/CA116593/MONDO:0009290/010/el/0/1825/1827", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA116593/MONDO:0009290/010/ci/CA116593/MONDO:0009290/010.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50009_EP157972030954718", "id": "CG-PCER-AGENT:CG_50009_EP157972030954718", "type": "Agent" }, "comments": "In a case study of siblings homozygous for this variant (PMID: 1898413), GAA activity was undetectable in patient fibroblasts, and the GAA precursor was about 5kD smaller than the expected 110kD wild type precursor on SDS PAGE. An in vitro study revealed that the translation product of Glu521Lys does run about 5 kD ahead of the wilt type, both unglycosylated and glycoslated forms. Transient expression in COS cells revealed no detectable activity above background. Immunocytochemistry results suggest the mutant precursor is not transported to the lysosomes. In a later functional study (PMID: 19862843), expression of the variant in COS-7 cells resulted in <2% wild type GAA activity, indicating that this variant may impact protein function (PS3_supporting). ", "contributionDate": { "date": "2024/12/17", "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": "CA116593/MONDO:0009290/010/ci/CA116593/MONDO:0009290/010.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA116593/MONDO:0009290/010/0/1825/1827", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA116593/MONDO:0009290/010/1/1826", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA116593/MONDO:0009290/010/0/1825", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA116593/MONDO:0009290/010/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA116593/MONDO:0009290/010/ei/1/1748", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50009_EP157972030954718", "id": "CG-PCER-AGENT:CG_50009_EP157972030954718", "type": "Agent" }, "contributionDate": { "date": "2024/12/17", "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/CA116593/MONDO:0009290/010/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA116593/MONDO:0009290/010/ci/CA116593/MONDO:0009290/010.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50009_EP157972030954718", "id": "CG-PCER-AGENT:CG_50009_EP157972030954718", "type": "Agent" }, "comments": "The computational predictor REVEL gives a score of 0.932 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3).", "contributionDate": { "date": "2024/12/17", "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": "CA116593/MONDO:0009290/010/ci/CA116593/MONDO:0009290/010.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA116593/MONDO:0009290/010/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA116593/MONDO:0009290/010/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA116593/MONDO:0009290/010/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA116593/MONDO:0009290/010/el/0/1780", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA116593/MONDO:0009290/010/ei/1/1781", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50009_EP157972030954718", "id": "CG-PCER-AGENT:CG_50009_EP157972030954718", "type": "Agent" }, "contributionDate": { "date": "2024/12/17", "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/CA116593/MONDO:0009290/010/el/0/1780/1782", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA116593/MONDO:0009290/010/ci/CA116593/MONDO:0009290/010.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50009_EP157972030954718", "id": "CG-PCER-AGENT:CG_50009_EP157972030954718", "type": "Agent" }, "comments": "c.1561G>C (p.Glu521Gln) has been reported in IOPD (PMIDs: 22658377, 19588081) but has not been reviewed by the VCEP and therefore PM5 will not be applied. ClinVar ID: 2736677", "contributionDate": { "date": "2024/12/17", "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": "CA116593/MONDO:0009290/010/ci/CA116593/MONDO:0009290/010.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA116593/MONDO:0009290/010/0/1780/1782", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA116593/MONDO:0009290/010/1/1781", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA116593/MONDO:0009290/010/0/1780", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA116593/MONDO:0009290/010", "metadata": { "created": "2024-12-20T22:55:46.665Z", "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": "Fri, 20 Dec 2024 22:55:46 -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": "be2941a7-23d4-4e6f-b888-bdfd4c496ba5", "variant": { "@id": "https://reg.genome.network/allele/CA116593", "id": "CAR:CA116593", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000152.4:c.1561G>A" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000152.4(GAA):c.1561G>A (p.Glu521Lys)" } ], "type": "CAR" } } ], "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-10-23T21:53:25.724Z" } }, "status": { "code": 200, "name": "OK" } }