{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T17:09:35Z","timestamp":1784740175526,"version":"3.55.0"},"reference-count":38,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2019,5]]},"abstract":"<jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>\n              Many rare, potentially pathogenic,\n              <jats:italic>RYR2<\/jats:italic>\n              variants identified in individuals with clinically definite catecholaminergic polymorphic ventricular tachycardia are classified ambiguously as variants of uncertain significance (VUS). We aimed to determine if a phenotype-enhanced variant classification approach could reduce the burden of\n              <jats:italic>RYR2<\/jats:italic>\n              VUS encountered during clinical genetic testing.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>\n              This retrospective study was conducted in 84\n              <jats:italic>RYR2<\/jats:italic>\n              -positive individuals from the Mayo Clinic (Rochester, MN) and validated in 149\n              <jats:italic>RYR2<\/jats:italic>\n              -positive individuals from Amsterdam University Medical Center (Amsterdam, NL). Using a newly developed diagnostic scorecard, the pretest clinical probability of catecholaminergic polymorphic ventricular tachycardia was determined for all\n              <jats:italic>RYR2<\/jats:italic>\n              -positive individuals. Each\n              <jats:italic>RYR2<\/jats:italic>\n              variant was then readjudicated using a phenotype-enhanced American College of Medical Genetics approach that incorporates new criteria that reflect the phenotypic strength associated with each individual\n              <jats:italic>RYR2<\/jats:italic>\n              variant.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>\n              Overall, 72 distinct\n              <jats:italic>RYR2<\/jats:italic>\n              variants were identified among the 84 Mayo Clinic (39 unique) and 149 Amsterdam University Medical Center (30 unique) cases. Three variants were present in both cohorts. American College of Medical Genetics guidelines classified 47% of all\n              <jats:italic>RYR2<\/jats:italic>\n              variants as VUS. In the Mayo Clinic cohort, readjudication using amended phenotype-enhanced American College of Medical Genetics standards dropped the VUS rate significantly (20\/42 [48%] versus 3\/42 [7%];\n              <jats:italic>P<\/jats:italic>\n              &lt;0.001) with 13\/20 (65%)\n              <jats:italic>RYR2<\/jats:italic>\n              VUS promoted to likely pathogenic and 4\/20 (20%) demoted to likely benign. A similar drop in VUS rate (14\/33 [42%] versus 3\/33 [9%];\n              <jats:italic>P<\/jats:italic>\n              =0.001) was observed in the Amsterdam University Medical Center validation cohort with 10\/14 (71%)\n              <jats:italic>RYR2<\/jats:italic>\n              VUS promoted to likely pathogenic and 1\/14 (7%) demoted to likely benign.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>This multicenter study illustrates the potential utility of phenotype-enhanced variant classification in catecholaminergic polymorphic ventricular tachycardia.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circgen.119.002510","type":"journal-article","created":{"date-parts":[[2019,5,21]],"date-time":"2019-05-21T18:08:43Z","timestamp":1558462123000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":56,"title":["Assessment and Validation of a Phenotype-Enhanced Variant Classification Framework to Promote or Demote\n            <i>RYR2<\/i>\n            Missense Variants of Uncertain Significance"],"prefix":"10.1161","volume":"12","author":[{"given":"John R.","family":"Giudicessi","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Medicine (Clinician-Investigator Training Program) (J.R.G.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krystien V.V.","family":"Lieve","sequence":"additional","affiliation":[{"name":"Amsterdam UMC, University of Amsterdam, Heart Center and Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, The Netherlands (K.V.V.L., F.K., C.v.d.W., A.A.M.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ram K.","family":"Rohatgi","sequence":"additional","affiliation":[{"name":"Department of Pediatric and Adolescent Medicine (Division of Pediatric Cardiology) (R.K.R.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faruk","family":"Koca","sequence":"additional","affiliation":[{"name":"Amsterdam UMC, University of Amsterdam, Heart Center and Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, The Netherlands (K.V.V.L., F.K., C.v.d.W., A.A.M.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Tester","sequence":"additional","affiliation":[{"name":"Departments of Cardiovascular Medicine (Division of Heart Rhythm Services), Pediatrics (Division of Pediatric Cardiology), and Molecular Pharmacology and Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, MN (D.J.T., J.M.B., M.J.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"van der Werf","sequence":"additional","affiliation":[{"name":"Amsterdam UMC, University of Amsterdam, Heart Center and Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, The Netherlands (K.V.V.L., F.K., C.v.d.W., A.A.M.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Martijn Bos","sequence":"additional","affiliation":[{"name":"Departments of Cardiovascular Medicine (Division of Heart Rhythm Services), Pediatrics (Division of Pediatric Cardiology), and Molecular Pharmacology and Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, MN (D.J.T., J.M.B., M.J.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur A.M.","family":"Wilde","sequence":"additional","affiliation":[{"name":"Amsterdam UMC, University of Amsterdam, Heart Center and Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, The Netherlands (K.V.V.L., F.K., C.v.d.W., A.A.M.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael 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