{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T18:45:23Z","timestamp":1776797123278,"version":"3.51.2"},"reference-count":36,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      Catecholaminergic polymorphic ventricular tachycardia (CPVT) is strongly associated with rare missense variants in\n                      <jats:italic toggle=\"yes\">RYR2<\/jats:italic>\n                      , the gene encoding the intracellular calcium release channel RyR2.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      We curated 179 articles reviewed by 3 individuals to extrapolate\n                      <jats:italic toggle=\"yes\">RYR2<\/jats:italic>\n                      -CPVT missense variant genotype-phenotype relationships. Purportedly neutral control variants were ascertained from\n                      <jats:italic toggle=\"yes\">RYR2<\/jats:italic>\n                      missense variants observed in gnomAD and ClinVar. We performed an\n                      <jats:italic toggle=\"yes\">RYR2<\/jats:italic>\n                      -CPVT Bayesian penetrance analysis by conditioning a CPVT penetrance prior (hereafter called Bayesian CPVT-prior) on variant-specific features (in silico and structural) calibrated by heterozygote phenotypes. We evaluated various features, including the Bayesian CPVT-prior, ClinVar, REVEL, and AlphaMissense against our observed CPVT penetrance, using Spearman rank-order correlations and Brier Scores. Penetrance estimates were superimposed on a cryo-EM structure of RyR2 to investigate hot-spot heterogeneity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      From the literature, we identified 1014 affected missense\n                      <jats:italic toggle=\"yes\">RYR2<\/jats:italic>\n                      heterozygotes (468 unique variants), and further supplemented by purpuroted unaffected heterozygotes in GnomAD to a total of 622\u2009575 heterozygotes (5181 unique variants). Among the predictors, the Bayesian CPVT-prior score had the highest Spearman rank-order and lowest Brier scores, respectively (0.19; 0.0090), compared with ClinVar (0.083; 0.019), REVEL (0.16; 0.018), or AlphaMissense (0.18; 0.018). Penetrance estimates for all\n                      <jats:italic toggle=\"yes\">RYR2<\/jats:italic>\n                      missense variants are prospectively hosted at the Variant Browser website.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Traditional categorical variant annotations limit accurate disease risk assessment, especially in populations unascertained for disease. A probabilistic, population-calibrated penetrance framework enables more meaningful prospective variant interpretation. Our Bayesian CPVT-prior outperforms current tools in evaluating RYR2 variant penetrance. We provide prospective Bayesian CPVT penetrance values for 29\u2009242 RYR2 missense variants at our online variant browser.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circgen.125.005457","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T09:00:08Z","timestamp":1774602008000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Structural Evaluation of\n                    <i>RYR2<\/i>\n                    -CPVT Missense Variants and Continuous Bayesian Estimates of Their Penetrance"],"prefix":"10.1161","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1360-7939","authenticated-orcid":true,"given":"Kundivy","family":"Dauda","sequence":"first","affiliation":[{"name":"Division of Genetic Medicine and Clinical Pharmacology, Department of Medicine (K.D., M.K., D.W.M., A.S., L.V., B.C.K., B.M.K.)"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0348-2305","authenticated-orcid":true,"given":"Kohei","family":"Yamauchi","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Shiga University of Medical Science, Otsu, Japan (K.Y.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew","family":"Ku","sequence":"additional","affiliation":[{"name":"Division of Genetic Medicine and Clinical Pharmacology, Department of Medicine (K.D., M.K., D.W.M., A.S., L.V., B.C.K., B.M.K.)"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8508-3324","authenticated-orcid":true,"given":"Devyn W.","family":"Mitchell","sequence":"additional","affiliation":[{"name":"Division of Genetic Medicine and Clinical Pharmacology, Department of Medicine (K.D., M.K., D.W.M., A.S., L.V., B.C.K., B.M.K.)"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8430-8357","authenticated-orcid":true,"given":"Alex","family":"Shen","sequence":"additional","affiliation":[{"name":"Division of Genetic Medicine and Clinical Pharmacology, Department of Medicine (K.D., M.K., D.W.M., A.S., L.V., B.C.K., B.M.K.)"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5950-2777","authenticated-orcid":true,"given":"Loren","family":"Vanags","sequence":"additional","affiliation":[{"name":"Division of Genetic Medicine and Clinical Pharmacology, Department of Medicine (K.D., M.K., D.W.M., A.S., L.V., B.C.K., B.M.K.)"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9437-5871","authenticated-orcid":true,"given":"Jeffrey","family":"Schmeckpeper","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine (J.S.), Monroe Carell Jr. Children\u2019s Hospital at Vanderbilt, Vanderbilt University Medical Center, Nashville, TN."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1529-9872","authenticated-orcid":true,"given":"Prince J.","family":"Kannankeril","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (P.J.K.), Monroe Carell Jr. Children\u2019s Hospital at Vanderbilt, Vanderbilt University Medical Center, Nashville, TN."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4956-9735","authenticated-orcid":true,"given":"Bjorn C.","family":"Knollmann","sequence":"additional","affiliation":[{"name":"Division of Genetic Medicine and Clinical Pharmacology, Department of Medicine (K.D., M.K., D.W.M., A.S., L.V., B.C.K., B.M.K.)"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew J.","family":"O\u2019Neill","sequence":"additional","affiliation":[{"name":"Department of Medicine, Brigham and Women\u2019s Hospital, Boston, MA (M.J.O.)."},{"name":"Clinical Fellow, Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA (M.J.O.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6215-0803","authenticated-orcid":true,"given":"Brett M.","family":"Kroncke","sequence":"additional","affiliation":[{"name":"Division of Genetic Medicine and Clinical Pharmacology, Department of Medicine (K.D., M.K., D.W.M., A.S., L.V., B.C.K., 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