{ "sequenceReference": { "SQ.6CnHhDq_bDCsuIBf0AzxtKq_lXYM7f0m": { "type": "SequenceReference", "refgetAccession": "SQ.6CnHhDq_bDCsuIBf0AzxtKq_lXYM7f0m" }, "SQ.EJQv9rQmiD76iFmXsLwCy2dJHOFO3bpj": { "type": "SequenceReference", "refgetAccession": "SQ.EJQv9rQmiD76iFmXsLwCy2dJHOFO3bpj" }, "SQ.pnAqCRBrTsUoBghSD1yp_jXWSmlbdh4g": { "type": "SequenceReference", "refgetAccession": "SQ.pnAqCRBrTsUoBghSD1yp_jXWSmlbdh4g" } }, "location": { "ga4gh:SL.DO4BZ8csWCDedM5lh7NrmIpS3RnboBHw": { "id": "ga4gh:SL.DO4BZ8csWCDedM5lh7NrmIpS3RnboBHw", "type": "SequenceLocation", "digest": "DO4BZ8csWCDedM5lh7NrmIpS3RnboBHw", "sequenceReference": "#/sequenceReference/SQ.EJQv9rQmiD76iFmXsLwCy2dJHOFO3bpj", "start": 1699, "end": 1700, "sequence": "G" }, "ga4gh:SL.ET6dAkJ468aUfP3iLEWuG_Yfl_gFMDq0": { "id": "ga4gh:SL.ET6dAkJ468aUfP3iLEWuG_Yfl_gFMDq0", "type": "SequenceLocation", "digest": "ET6dAkJ468aUfP3iLEWuG_Yfl_gFMDq0", "sequenceReference": "#/sequenceReference/SQ.pnAqCRBrTsUoBghSD1yp_jXWSmlbdh4g", "start": 157766003, "end": 157766004, "sequence": "C" }, "ga4gh:SL.cOMztEW7PBkzDSr_gkVyzfYDcmH8fp3G": { "id": "ga4gh:SL.cOMztEW7PBkzDSr_gkVyzfYDcmH8fp3G", "type": "SequenceLocation", "digest": "cOMztEW7PBkzDSr_gkVyzfYDcmH8fp3G", "sequenceReference": "#/sequenceReference/SQ.6CnHhDq_bDCsuIBf0AzxtKq_lXYM7f0m", "start": 327, "end": 328, "sequence": "G" } }, "variant": { "civic.vid:1686": { "protein": { "ga4gh:VA.fcWuwB4g25bTPp52iyTF7DnBNPm5POer": { "id": "ga4gh:VA.fcWuwB4g25bTPp52iyTF7DnBNPm5POer", "type": "Allele", "name": "ACVR1 G328V", "digest": "fcWuwB4g25bTPp52iyTF7DnBNPm5POer", "expressions": [ { "syntax": "hgvs.p", "value": "NP_001096.1:p.Gly328Val" }, { "syntax": "hgvs.p", "value": "NP_001104537.1:p.Gly328Val" }, { "syntax": "hgvs.p", "value": "ENSP00000405004.1:p.Gly328Val" } ], "location": "#/location/ga4gh:SL.cOMztEW7PBkzDSr_gkVyzfYDcmH8fp3G", "state": { "type": "LiteralSequenceExpression", "sequence": "V" } } }, "coding": { "ga4gh:VA.knLN28eRu0f2IUAQBHwXjvjyKyNNwb9N": { "id": "ga4gh:VA.knLN28eRu0f2IUAQBHwXjvjyKyNNwb9N", "type": "Allele", "name": "NM_001111067.4:c.983G>T", "digest": "knLN28eRu0f2IUAQBHwXjvjyKyNNwb9N", "expressions": [ { "syntax": "hgvs.c", "value": "NM_001105.4:c.983G>T" }, { "syntax": "hgvs.c", "value": "NM_001111067.4:c.983G>T" } ], "location": "#/location/ga4gh:SL.DO4BZ8csWCDedM5lh7NrmIpS3RnboBHw", "state": { "type": "LiteralSequenceExpression", "sequence": "T" } } }, "genomic": { "ga4gh:VA.affc26OivYhQEhNjs0NS2f3-2BYoEsey": { "id": "ga4gh:VA.affc26OivYhQEhNjs0NS2f3-2BYoEsey", "type": "Allele", "name": "NC_000002.12:g.157766004C>A", "digest": "affc26OivYhQEhNjs0NS2f3-2BYoEsey", "expressions": [ { "syntax": "hgvs.g", "value": "NC_000002.11:g.158622516C>A" }, { "syntax": "hgvs.g", "value": "NC_000002.12:g.157766004C>A" } ], "location": "#/location/ga4gh:SL.ET6dAkJ468aUfP3iLEWuG_Yfl_gFMDq0", "state": { "type": "LiteralSequenceExpression", "sequence": "A" } } } }, "civic.vid:2061": { "unsupported": { "id": "civic.vid:2061", "extensions": [ { "name": "subtype", "value": "gene_variant" } ], "name": "Gain-of-Function", "system": "https://civicdb.org/links/variant/", "code": "2061" } } }, "feature": { "civic.gid:154": { "id": "civic.gid:154", "extensions": [ { "name": "aliases", "value": [ "ACTRI", "ACVR1", "ACVR1A", "ACVRLK2", "ALK2", "FOP", "SKR1", "TSRI" ] } ], "conceptType": "Gene", "name": "ACVR1", "mappings": [ { "coding": { "id": "ncbigene:90", "system": "https://www.ncbi.nlm.nih.gov/gene/", "code": "90" }, "relation": "exactMatch" } ] } }, "molecularProfile": { "civic.mpid:1594": { "id": "civic.mpid:1594", "type": "CategoricalVariant", "name": "ACVR1 G328V", "aliases": [ "GLY328VAL" ], "extensions": [ { "name": "molecularProfileScore", "value": 35.0 }, { "name": "hgvsDescriptions", "value": [ "NM_001105.4:c.983G>T", "NP_001096.1:p.Gly328Val", "NC_000002.11:g.158622516C>A", "ENST00000434821.1:c.983G>T", "NC_000002.12:g.157766004C>A", "NM_001111067.4:c.983G>T", "NP_001104537.1:p.Gly328Val", "ENST00000434821.7:c.983G>T", "ENSP00000405004.1:p.Gly328Val" ] }, { "name": "maneSelectTranscript", "value": "ENST00000434821.7:c.983G>T" }, { "name": "representativeVariantCoordinates", "value": { "chromosome": "2", "start": 158622516, "stop": 158622516, "reference_bases": "C", "variant_bases": "A", "ensembl_version": 75, "representative_transcript": "ENST00000434821.1", "reference_build": "GRCh37", "type": "coordinates" } }, { "name": "categoricalVariationType", "value": "ProteinSequenceConsequence" } ], "members": [ "#/variant/civic.vid:1686/coding/ga4gh:VA.knLN28eRu0f2IUAQBHwXjvjyKyNNwb9N", "#/variant/civic.vid:1686/genomic/ga4gh:VA.affc26OivYhQEhNjs0NS2f3-2BYoEsey", "#/variant/civic.vid:1686/protein/ga4gh:VA.fcWuwB4g25bTPp52iyTF7DnBNPm5POer" ], "constraints": [ { "type": "DefiningAlleleConstraint", "allele": "#/variant/civic.vid:1686/protein/ga4gh:VA.fcWuwB4g25bTPp52iyTF7DnBNPm5POer", "relations": [ { "primaryCoding": { "system": "ga4gh-gks-term:allele-relation", "code": "liftover_to" } }, { "primaryCoding": { "system": "http://www.sequenceontology.org", "code": "translation_of" } } ] } ], "mappings": [ { "coding": "#/molecularProfile/civic.mpid:1594", "relation": "exactMatch" }, { "coding": { "id": "civic.vid:1686", "extensions": [ { "name": "subtype", "value": "gene_variant" }, { "name": "variantTypes", "value": [ { "coding": { "id": "civic.variant_type:47", "name": "Missense Variant", "system": "http://www.sequenceontology.org/browser/current_svn/term/", "code": "SO:0001583" }, "relation": "exactMatch" } ] } ], "name": "G328V", "system": "https://civicdb.org/links/variant/", "code": "1686" }, "relation": "exactMatch" }, { "coding": { "id": "clingen.allele:CA16602802", "system": "https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_canonicalid?canonicalid=", "code": "CA16602802" }, "relation": "relatedMatch" }, { "coding": { "id": "clinvar:376363", "system": "https://www.ncbi.nlm.nih.gov/clinvar/variation/", "code": "376363" }, "relation": "relatedMatch" }, { "coding": { "id": "dbsnp:rs387906589", "system": "https://www.ncbi.nlm.nih.gov/snp/", "code": "rs387906589" }, "relation": "relatedMatch" } ] }, "civic.mpid:1937": { "id": "civic.mpid:1937", "type": "CategoricalVariant", "name": "ACVR1 Gain-of-Function", "extensions": [ { "name": "molecularProfileScore", "value": 15.0 }, { "name": "hgvsDescriptions", "value": [] }, { "name": "categoricalVariationType", "value": "Undefined" } ], "mappings": [ { "coding": "#/molecularProfile/civic.mpid:1937", "relation": "exactMatch" }, { "coding": { "id": "civic.vid:2061", "extensions": [ { "name": "subtype", "value": "gene_variant" } ], "name": "Gain-of-Function", "system": "https://civicdb.org/links/variant/", "code": "2061" }, "relation": "exactMatch" } ] } }, "disease": { "civic.did:2950": { "id": "civic.did:2950", "conceptType": "Disease", "name": "Diffuse Midline Glioma, H3 K27-altered", "mappings": [ { "coding": { "system": "https://disease-ontology.org/?id=", "code": "DOID:0080684" }, "relation": "exactMatch" } ] } }, "phenotype": {}, "conditionSet": {}, "therapy": {}, "therapyGroup": {}, "variantOrigin": { "civic.variantOrigin:SOMATIC": { "id": "civic.variantOrigin:SOMATIC", "name": "somatic", "mappings": [ { "coding": { "system": "https://civicdb.org", "code": "SOMATIC", "iris": [ "https://civic.readthedocs.io/en/latest/model/evidence/origin.html" ] }, "relation": "exactMatch" } ] } }, "source": { "civic.sid:2149": { "id": "civic.sid:2149", "type": "Document", "name": "Fontebasso et al., 2014", "title": "Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma.", "urls": [ "https://civicdb.org/links/evidence/4846", "https://civicdb.org/links/source/2149", "http://www.ncbi.nlm.nih.gov/pubmed/24705250", "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4282994" ], "pmid": "24705250" }, "civic.sid:2680": { "id": "civic.sid:2680", "type": "Document", "name": "Buczkowicz et al., 2014", "title": "Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations.", "urls": [ "https://civicdb.org/links/evidence/6955", "https://civicdb.org/links/source/2680", "http://www.ncbi.nlm.nih.gov/pubmed/24705254", "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3997489" ], "pmid": "24705254" }, "pmid:31779674": { "id": "pmid:31779674", "type": "Document", "name": "Danos et al., 2019, Genome Med.", "aliases": [ "CIViC curation SOP" ], "title": "Standard operating procedure for curation and clinical interpretation of variants in cancer", "urls": [ "https://doi.org/10.1186/s13073-019-0687-x", "https://pubmed.ncbi.nlm.nih.gov/31779674/" ], "doi": "10.1186/s13073-019-0687-x", "pmid": "31779674" } }, "method": { "civic.method:2019": { "id": "civic.method:2019", "type": "Method", "name": "CIViC Curation SOP (2019)", "methodType": "curation", "reportedIn": "#/source/pmid:31779674" } }, "organization": {}, "proposition": { "civic.proposition:f0SrtLbW05PqfqLs-hOK4tZxI3xO3kMO": { "id": "civic.proposition:f0SrtLbW05PqfqLs-hOK4tZxI3xO3kMO", "type": "VariantClinicalSignificanceProposition", "subjectVariant": "#/molecularProfile/civic.mpid:1594", "geneContextQualifier": "#/feature/civic.gid:154", "alleleOriginQualifier": "#/variantOrigin/civic.variantOrigin:SOMATIC", "predicate": "hasClinicalSignificanceFor", "objectCondition": "#/disease/civic.did:2950" }, "civic.proposition:gGPvwGKtZSs7Me0eqveHyfB2zKj1QXX6": { "id": "civic.proposition:gGPvwGKtZSs7Me0eqveHyfB2zKj1QXX6", "type": "VariantDiagnosticProposition", "subjectVariant": "#/molecularProfile/civic.mpid:1594", "geneContextQualifier": "#/feature/civic.gid:154", "alleleOriginQualifier": "#/variantOrigin/civic.variantOrigin:SOMATIC", "predicate": "isDiagnosticInclusionCriterionFor", "objectCondition": "#/disease/civic.did:2950" }, "civic.proposition:ki9U_ovzggtVxDm1a9DXc8yWMKzGWOPK": { "id": "civic.proposition:ki9U_ovzggtVxDm1a9DXc8yWMKzGWOPK", "type": "VariantDiagnosticProposition", "subjectVariant": "#/molecularProfile/civic.mpid:1937", "geneContextQualifier": "#/feature/civic.gid:154", "alleleOriginQualifier": "#/variantOrigin/civic.variantOrigin:SOMATIC", "predicate": "isDiagnosticInclusionCriterionFor", "objectCondition": "#/disease/civic.did:2950" } }, "evidence": { "civic.eid:4846": { "id": "civic.eid:4846", "type": "Statement", "description": "Sequencing of 39 pediatric midline high-grade astrocytomas identified 5 patients with ACVR1 mutations. The authors identified an increase in endogenous phospho-SMAD1/5/8 signal in diffuse intrinsic pontine glioma (DIPG) cells harboring ACVR1 G328V, with corresponding increase in phospho-SMAD1/5/8 staining as well. By PCR, the authors show strong increase in fold change of mRNA expression in downstream proteins of the ACVR1/BMP pathway, ID, ID2, ID3 and SNAI1 in ACVR1-mutant DIPG cell line compared to glioblastoma cells (KNS42 cells). These activating ACVR1 mutations were exclusively in midline high grade astrocytomas (P = 0.0040, Fisher's exact test).", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:2149" ], "proposition": "#/proposition/civic.proposition:ki9U_ovzggtVxDm1a9DXc8yWMKzGWOPK", "direction": "supports", "strength": { "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } }, "civic.eid:6955": { "id": "civic.eid:6955", "type": "Statement", "description": "In a study sequencing 61 patients (median age 6.3) with diffuse intrinsic pontine glioma (DIPG), 12 variants affecting ACVR1 were observed. Five patients had G328V within the kinase domain. The ACVR1 G328V mutation was expressed using the pCDH511b vector in immortalized normal human astrocytes (iNHAs) where it activated downstream BMP signaling and enhanced cell growth. Activating ACVR1 mutations are recurrent and support diagnosis of high grade glioma. PEDIATRIC", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "#/source/civic.sid:2680" ], "proposition": "#/proposition/civic.proposition:gGPvwGKtZSs7Me0eqveHyfB2zKj1QXX6", "direction": "supports", "strength": { "name": "Clinical evidence", "primaryCoding": { "system": "https://civic.readthedocs.io/en/latest/model/evidence/level.html", "code": "B" }, "mappings": [ { "coding": { "name": "clinical cohort evidence", "system": "https://go.osu.edu/evidence-codes", "code": "e000005" }, "relation": "exactMatch" } ] } } }, "assertion": { "civic.aid:9": { "id": "civic.aid:9", "type": "Statement", "description": "ACVR1 G328V mutations occur within the kinase domain, leading to activation of downstream signaling. Exclusively seen in high-grade pediatric gliomas, supporting diagnosis of diffuse intrinsic pontine glioma.", "specifiedBy": "#/method/civic.method:2019", "reportedIn": [ "https://civicdb.org/links/assertion/9", "#/source/civic.sid:2149", "#/source/civic.sid:2680" ], "proposition": "#/proposition/civic.proposition:f0SrtLbW05PqfqLs-hOK4tZxI3xO3kMO", "direction": "supports", "strength": { "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "potential" } }, "classification": { "name": "Tier II", "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "tier ii" } }, "hasEvidenceLines": [ { "type": "EvidenceLine", "targetProposition": "#/proposition/civic.proposition:gGPvwGKtZSs7Me0eqveHyfB2zKj1QXX6", "hasEvidenceItems": [ "#/evidence/civic.eid:4846", "#/evidence/civic.eid:6955" ], "directionOfEvidenceProvided": "supports", "strengthOfEvidenceProvided": { "primaryCoding": { "system": "AMP/ASCO/CAP Guidelines, 2017", "code": "C" } } } ] } }, "metadata": { "implementationVersions": { "VRSPython": "2.4.0a3.dev2+gdaceb0b6c", "CatVRSPython": "0.8.0a3.dev1+g30d6c5035", "VASpecPython": "0.5.0a4.dev7+gdaa80e6e8" }, "specificationVersions": { "GKSCore": "1.1.0", "VRS": "2.1.0-snapshot.2026-02.2", "CatVRS": "1.1.0-snapshot.2026-02.3", "VASpec": "1.1.0-snapshot.2026-06.1" }, "createdAt": "2026-09-02", "bundleFormat": "civic-gks-bundle", "bundleFormatVersion": "0.1.0", "statistics": { "collections": { "sequenceReference": { "count": 3 }, "location": { "count": 3, "types": { "SequenceLocation": 3 } }, "variant": { "count": 2, "types": { "Allele": 3, "Coding": 1 } }, "feature": { "count": 1 }, "molecularProfile": { "count": 2 }, "disease": { "count": 1 }, "phenotype": { "count": 0 }, "conditionSet": { "count": 0 }, "therapy": { "count": 0 }, "therapyGroup": { "count": 0 }, "variantOrigin": { "count": 1 }, "source": { "count": 3 }, "method": { "count": 1 }, "organization": { "count": 0 }, "proposition": { "count": 3, "types": { "VariantClinicalSignificanceProposition": 1, "VariantDiagnosticProposition": 2 } }, "evidence": { "count": 2 }, "assertion": { "count": 1 } } } }, "failedAssertionIds": [], "errors": [] }