{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://erepo.genome.network/evrepo/api/summary/classification/dfc87800-7035-4aa9-9521-7f9f9c031b40/doc/sepio/version/1.0.0", "assertionMethod": { "@id": "https://cspec.genome.network/cspec/SequenceVariantInterpretation/id/643243113", "label": "ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTPN11 Version 2.3.0", "type": "VariantPathogenicityInterpretationGuideline", "version": "2.3.0" }, "condition": { "@id": "https://api.monarchinitiative.org/api/bioentity/phenotype/MONDO:0021060", "id": "MONDO:0021060", "label": "RASopathy", "type": "GeneticCondition" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA235331/MONDO:0021060/043/el/0/1837", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA235331/MONDO:0021060/043/ei/1/1838", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50021_EP155190663717081", "id": "CG-PCER-AGENT:CG_50021_EP155190663717081", "type": "Agent" }, "contributionDate": { "date": "2025/9/25", "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/CA235331/MONDO:0021060/043/el/0/1837/1839", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA235331/MONDO:0021060/043/ci/CA235331/MONDO:0021060/043.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50021_EP155190663717081", "id": "CG-PCER-AGENT:CG_50021_EP155190663717081", "type": "Agent" }, "comments": "The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common. The Z-score for missense variants in PTPN11 in gnomAD v4.1.0 is 4.95 (PP2; PMID: 29493581).", "contributionDate": { "date": "2025/9/25", "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": "CA235331/MONDO:0021060/043/ci/CA235331/MONDO:0021060/043.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA235331/MONDO:0021060/043/0/1837/1839", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA235331/MONDO:0021060/043/1/1838", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA235331/MONDO:0021060/043/0/1837", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA235331/MONDO:0021060/043/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA235331/MONDO:0021060/043/ei/1/1748", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50021_EP155190663717081", "id": "CG-PCER-AGENT:CG_50021_EP155190663717081", "type": "Agent" }, "contributionDate": { "date": "2025/9/25", "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/CA235331/MONDO:0021060/043/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA235331/MONDO:0021060/043/ci/CA235331/MONDO:0021060/043.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50021_EP155190663717081", "id": "CG-PCER-AGENT:CG_50021_EP155190663717081", "type": "Agent" }, "comments": "The computational predictor REVEL gives a score of 0.9, which is above the RASopathy VCEP threshold of 0.7, evidence that correlates with impact to MAP2K1 function (PP3). In-silico predictors suggest harmful effect (ie. damaging by SIFT, FATHMM, & Provean; deleterious by SRT; disease-causing by mutation taster).", "contributionDate": { "date": "2025/9/25", "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": "CA235331/MONDO:0021060/043/ci/CA235331/MONDO:0021060/043.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA235331/MONDO:0021060/043/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA235331/MONDO:0021060/043/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA235331/MONDO:0021060/043/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA235331/MONDO:0021060/043/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA235331/MONDO:0021060/043/ei/1/1637", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50021_EP155190663717081", "id": "CG-PCER-AGENT:CG_50021_EP155190663717081", "type": "Agent" }, "contributionDate": { "date": "2025/9/25", "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/CA235331/MONDO:0021060/043/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA235331/MONDO:0021060/043/ci/CA235331/MONDO:0021060/043.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50021_EP155190663717081", "id": "CG-PCER-AGENT:CG_50021_EP155190663717081", "type": "Agent" }, "comments": "This variant is absent from gnomAD v2.1.1 (PM2_supporting). Coverage of the gene in this region is accurate.", "contributionDate": { "date": "2025/9/25", "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": "CA235331/MONDO:0021060/043/ci/CA235331/MONDO:0021060/043.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA235331/MONDO:0021060/043/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA235331/MONDO:0021060/043/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA235331/MONDO:0021060/043/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA235331/MONDO:0021060/043/el/0/1729", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA235331/MONDO:0021060/043/ei/1/1730", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50021_EP155190663717081", "id": "CG-PCER-AGENT:CG_50021_EP155190663717081", "type": "Agent" }, "contributionDate": { "date": "2025/9/25", "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/CA235331/MONDO:0021060/043/el/0/1729/1731", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA235331/MONDO:0021060/043/ci/CA235331/MONDO:0021060/043.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50021_EP155190663717081", "id": "CG-PCER-AGENT:CG_50021_EP155190663717081", "type": "Agent" }, "comments": "This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 4 individuals with Noonan Syndrome with Multiple Lentigines (PM6_strong, 3.5 points; CeGaT internal data (SCV001247473), PMIDs: 14961557, 15928039, 20954246). ", "contributionDate": { "date": "2025/9/25", "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": "CA235331/MONDO:0021060/043/ci/CA235331/MONDO:0021060/043.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA235331/MONDO:0021060/043/0/1729/1731", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA235331/MONDO:0021060/043/1/1730", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA235331/MONDO:0021060/043/0/1729", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA235331/MONDO:0021060/043/el/0/1825", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA235331/MONDO:0021060/043/ei/1/1826", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50021_EP155190663717081", "id": "CG-PCER-AGENT:CG_50021_EP155190663717081", "type": "Agent" }, "contributionDate": { "date": "2025/9/25", "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/CA235331/MONDO:0021060/043/el/0/1825/1827", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA235331/MONDO:0021060/043/ci/CA235331/MONDO:0021060/043.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50021_EP155190663717081", "id": "CG-PCER-AGENT:CG_50021_EP155190663717081", "type": "Agent" }, "comments": "Enzyme-catalyzed hydrolysis of p-nitrophenyl phosphate analysis in E. Coli indicated reduced catalytic speed for the mutant. A study in HEK293 cells showed that the mutant performed dephosphorylation with greater efficiency and exhibited atypical behavior in ERK pathways. Another analysis in E. Coli showed reduced increased dephosphorylation in the mutant. Each of these three assays indicate that the variant impacts protein function (PS3_moderate; PMIDs: 24935154, 26742426).", "contributionDate": { "date": "2025/9/25", "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": "CA235331/MONDO:0021060/043/ci/CA235331/MONDO:0021060/043.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA235331/MONDO:0021060/043/0/1825/1827", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA235331/MONDO:0021060/043/1/1826", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA235331/MONDO:0021060/043/0/1825", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA235331/MONDO:0021060/043/el/0/1735", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA235331/MONDO:0021060/043/ei/1/1736", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50021_EP155190663717081", "id": "CG-PCER-AGENT:CG_50021_EP155190663717081", "type": "Agent" }, "contributionDate": { "date": "2025/9/25", "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/CA235331/MONDO:0021060/043/el/0/1735/1737", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA235331/MONDO:0021060/043/ci/CA235331/MONDO:0021060/043.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50021_EP155190663717081", "id": "CG-PCER-AGENT:CG_50021_EP155190663717081", "type": "Agent" }, "comments": "This variant has been reported in 7 probands with clinical features of Noonan Syndrome with multiple lentigines (PS4; > 5.0 pts.; CeGaT (SCV001247473) & Ambry Genetics (SCV002708581) internal data, PMIDs: 14961557, 15928039, 20954246, 22528600).", "contributionDate": { "date": "2025/9/25", "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": "CA235331/MONDO:0021060/043/ci/CA235331/MONDO:0021060/043.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA235331/MONDO:0021060/043/0/1735/1737", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA235331/MONDO:0021060/043/1/1736", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA235331/MONDO:0021060/043/0/1735", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA235331/MONDO:0021060/043", "metadata": { "created": "2025-09-25T19:51:35.730Z", "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, 25 Sep 2025 19:51:35 -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": "dfc87800-7035-4aa9-9521-7f9f9c031b40", "variant": { "@id": "https://reg.genome.network/allele/CA235331", "id": "CAR:CA235331", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_002834.5:c.1517A>C" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_002834.5(PTPN11):c.1517A>C (p.Gln506Pro)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-06-07T02:21:31.770Z" } }, "status": { "code": 200, "name": "OK" } }