{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/eb575230-a9e5-477c-a8c9-b2b3b0f87e34/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/CA401365192/MONDO:0009290/010/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA401365192/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": "2025/5/6", "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/CA401365192/MONDO:0009290/010/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA401365192/MONDO:0009290/010/ci/CA401365192/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 0.000001695 (2/1179940 alleles)\nin the European (non-Finnish)] population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting).", "contributionDate": { "date": "2025/5/6", "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": "CA401365192/MONDO:0009290/010/ci/CA401365192/MONDO:0009290/010.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA401365192/MONDO:0009290/010/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA401365192/MONDO:0009290/010/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA401365192/MONDO:0009290/010/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA401365192/MONDO:0009290/010/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA401365192/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": "2025/5/6", "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/CA401365192/MONDO:0009290/010/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA401365192/MONDO:0009290/010/ci/CA401365192/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 0.968 which is above the threshold of\n0.7, evidence that correlates with impact to GAA function (PP3).", "contributionDate": { "date": "2025/5/6", "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": "CA401365192/MONDO:0009290/010/ci/CA401365192/MONDO:0009290/010.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA401365192/MONDO:0009290/010/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA401365192/MONDO:0009290/010/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA401365192/MONDO:0009290/010/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA401365192/MONDO:0009290/010/el/0/1696", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA401365192/MONDO:0009290/010/ei/1/1697", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50009_EP157972030954718", "id": "CG-PCER-AGENT:CG_50009_EP157972030954718", "type": "Agent" }, "contributionDate": { "date": "2025/5/6", "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/CA401365192/MONDO:0009290/010/el/0/1696/1698", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA401365192/MONDO:0009290/010/ci/CA401365192/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": "Expression of the GAA cDNA variant in HEK293T cells resulted in 12.6% wild type GAA activity in cells and 4.6% in culture media; however, intracellular amounts of the 110kDa precursor, 95 kDA intermediate, and 76 kDA mature forms of GAA in variant transfected cells were similar to the wild type transfected cells, suggesting that this variant does not interfere with the synthesis and processing of GAA, but results in a catalytic deficiency. In patient samples, expression of GAA mRNA extracted from muscle was approximately 4-fold lower than age and gender matched controls by qRT-PCR.", "contributionDate": { "date": "2025/5/6", "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": "CA401365192/MONDO:0009290/010/ci/CA401365192/MONDO:0009290/010.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA401365192/MONDO:0009290/010/0/1696/1698", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA401365192/MONDO:0009290/010/1/1697", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA401365192/MONDO:0009290/010/0/1696", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA401365192/MONDO:0009290/010/el/0/1831", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA401365192/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": "2025/5/6", "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/CA401365192/MONDO:0009290/010/el/0/1831/1833", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA401365192/MONDO:0009290/010/ci/CA401365192/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": "At least 2 individuals with this variant had documented GAA deficiency with <10% of normal\nmean control level of GAA activity in dry blood spot and muscle biopsy pathology consistent with Pompe disease (PMID: 24384324). One individual is an adult with diagnosis of late-onset Pompe disease receiving treatment with enzyme replacement therapy (ERT) and the other is a child diagnosed with CRIM-positive infantile-onset Pompe disease receiving treatment with ERT.", "contributionDate": { "date": "2025/5/6", "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": "CA401365192/MONDO:0009290/010/ci/CA401365192/MONDO:0009290/010.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA401365192/MONDO:0009290/010/0/1831/1833", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA401365192/MONDO:0009290/010/1/1832", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA401365192/MONDO:0009290/010/0/1831", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA401365192/MONDO:0009290/010/el/0/1615", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA401365192/MONDO:0009290/010/ei/1/1616", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50009_EP157972030954718", "id": "CG-PCER-AGENT:CG_50009_EP157972030954718", "type": "Agent" }, "contributionDate": { "date": "2025/5/6", "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/CA401365192/MONDO:0009290/010/el/0/1615/1617", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA401365192/MONDO:0009290/010/ci/CA401365192/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 alters amino acid Asp404, a residue that crystallography studies have shown to be\nimportant in the active site of GAA, and therefore has been defined as a critical residue by the\nClinGen Lysosomal Diseases VCEP (https://www.biorxiv.org/content/10.1101/212837v1.full.pdf,\nPMID: 29061980) (PM1).", "contributionDate": { "date": "2025/5/6", "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": "CA401365192/MONDO:0009290/010/ci/CA401365192/MONDO:0009290/010.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA401365192/MONDO:0009290/010/0/1615/1617", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA401365192/MONDO:0009290/010/1/1616", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA401365192/MONDO:0009290/010/0/1615", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA401365192/MONDO:0009290/010/el/0/1717", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA401365192/MONDO:0009290/010/ei/1/1718", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50009_EP157972030954718", "id": "CG-PCER-AGENT:CG_50009_EP157972030954718", "type": "Agent" }, "contributionDate": { "date": "2025/5/6", "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/CA401365192/MONDO:0009290/010/el/0/1717/1719", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA401365192/MONDO:0009290/010/ci/CA401365192/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": "At least one individual with Pompe disease was compound heterozygous for the variant and another pathogenic variant confirmed in trans by parental testing. This variant has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP (ClinVar ID: 640911)", "contributionDate": { "date": "2025/5/6", "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": "CA401365192/MONDO:0009290/010/ci/CA401365192/MONDO:0009290/010.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA401365192/MONDO:0009290/010/0/1717/1719", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA401365192/MONDO:0009290/010/1/1718", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA401365192/MONDO:0009290/010/0/1717", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA401365192/MONDO:0009290/010/el/0/1780", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA401365192/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": "2025/5/6", "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/CA401365192/MONDO:0009290/010/el/0/1780/1782", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA401365192/MONDO:0009290/010/ci/CA401365192/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": "Another missense variant [c.1210G>A, p.Asp404Asn] [PMIDs, ClinVar Variation ID: 657348 \nin the same codon has been classified as pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP. PM5 not applied given that this is a known active site and PM1 is applied. Three different missense variants, c.1211A>C (p.Asp404Ala), c.1211A>T (p.Asp404Val), and c.1212C>G (p.Asp404Glu), in the same codon have been reported in patients with Pompe disease (see http://www.pompevariantdatabase.nl/).", "contributionDate": { "date": "2025/5/6", "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": "CA401365192/MONDO:0009290/010/ci/CA401365192/MONDO:0009290/010.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA401365192/MONDO:0009290/010/0/1780/1782", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA401365192/MONDO:0009290/010/1/1781", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA401365192/MONDO:0009290/010/0/1780", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA401365192/MONDO:0009290/010", "metadata": { "created": "2025-05-15T16:25:31.240Z", "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 May 2025 16:25:31 -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": "eb575230-a9e5-477c-a8c9-b2b3b0f87e34", "variant": { "@id": "https://reg.genome.network/allele/CA401365192", "id": "CAR:CA401365192", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000152.5:c.1211A>G" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000152.5(GAA):c.1211A>G (p.Asp404Gly)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-11-01T03:05:12.032Z" } }, "status": { "code": 200, "name": "OK" } }