{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T23:12:34Z","timestamp":1770678754760,"version":"3.49.0"},"reference-count":99,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2021,8]]},"abstract":"<jats:p>Recent advances in next-genetic sequencing technology have facilitated an expansion in the use of exome and genome sequencing in the research and clinical settings. While this has aided in the genetic diagnosis of individuals with atypical clinical presentations, there has been a marked increase in the number of incidentally identified variants of uncertain diagnostic significance in genes identified as clinically actionable by the American College of Medical Genetics guidelines. Approximately 20 of these genes are associated with cardiac diseases, which carry a significant risk of sudden cardiac death. While identification of at-risk individuals is paramount, increased discovery of incidental variants of uncertain diagnostic significance has placed a burden on the clinician tasked with determining the diagnostic significance of these findings. Herein, we describe the scope of this emerging problem using cardiovascular genetics to illustrate the challenges associated with variants of uncertain diagnostic significance interpretation. We review the evidence for diagnostic weight of these variants, discuss the role of clinical genetics providers in patient care, and put forward general recommendations about the interpretation of incidentally identified variants found with clinical genetic testing.<\/jats:p>","DOI":"10.1161\/circgen.120.003200","type":"journal-article","created":{"date-parts":[[2021,8,13]],"date-time":"2021-08-13T09:00:44Z","timestamp":1628845244000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":14,"title":["Interpretation of Incidental Genetic Findings Localizing to Genes Associated With Cardiac Channelopathies and Cardiomyopathies"],"prefix":"10.1161","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3007-2078","authenticated-orcid":true,"given":"Jordan E.","family":"Ezekian","sequence":"first","affiliation":[{"name":"Division of Cardiology, Department of Pediatrics (J.E.E., A.P.L.), Duke University School of Medicine, Durham, NC."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4924-9010","authenticated-orcid":true,"given":"Catherine","family":"Rehder","sequence":"additional","affiliation":[{"name":"Department of Pathology (C.R.), Duke University School of Medicine, Durham, NC."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Priya S.","family":"Kishnani","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Department of Pediatrics (P.S.K.), Duke University School of Medicine, Durham, NC."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew P.","family":"Landstrom","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Pediatrics (J.E.E., A.P.L.), Duke University School of Medicine, Durham, NC."},{"name":"Department of Cell Biology (A.P.L.), Duke University School of Medicine, Durham, NC."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"e_1_3_6_2_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-015-1631-9"},{"key":"e_1_3_6_3_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2011-100223"},{"key":"e_1_3_6_4_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1306555"},{"key":"e_1_3_6_5_2","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2015.00067"},{"key":"e_1_3_6_6_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2014.14601"},{"key":"e_1_3_6_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2014.151"},{"key":"e_1_3_6_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_3_6_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2016.190"},{"key":"e_1_3_6_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2013.73"},{"key":"e_1_3_6_11_2","doi-asserted-by":"publisher","DOI":"10.1097\/GIM.0b013e3181f9ad55"},{"key":"e_1_3_6_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2020.05.002"},{"key":"e_1_3_6_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41431-017-0043-9"},{"key":"e_1_3_6_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2017.269"},{"key":"e_1_3_6_15_2","doi-asserted-by":"publisher","DOI":"10.1111\/jce.13355"},{"key":"e_1_3_6_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2016.90"},{"key":"e_1_3_6_17_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.119.043131"},{"key":"e_1_3_6_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0167-z"},{"key":"e_1_3_6_19_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.23996"},{"key":"e_1_3_6_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2016.193"},{"key":"e_1_3_6_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2016.06.001"},{"key":"e_1_3_6_22_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2015.17701"},{"key":"e_1_3_6_23_2","volume-title":"Direct-To-Consumer Genetic Testing: Summary of a Workshop","author":"Council NR","year":"2010","unstructured":"Council, NR. Direct-To-Consumer Genetic Testing: Summary of a Workshop.The National Academies Press; 2010."},{"key":"e_1_3_6_24_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.281.6240.592"},{"key":"e_1_3_6_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2018.02.031"},{"key":"e_1_3_6_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0025-6196(11)61527-9"},{"key":"e_1_3_6_27_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000066323.15244.54"},{"key":"e_1_3_6_28_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12265-014-9542-z"},{"key":"e_1_3_6_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2012.07.017"},{"key":"e_1_3_6_30_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20862"},{"key":"e_1_3_6_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2017.40"},{"key":"e_1_3_6_32_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGEN.119.002579"},{"key":"e_1_3_6_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardfail.2012.01.013"},{"key":"e_1_3_6_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2013.204"},{"key":"e_1_3_6_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-29263-3"},{"key":"e_1_3_6_36_2","doi-asserted-by":"publisher","DOI":"10.1002\/mgg3.245"},{"key":"e_1_3_6_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrcardio.2013.105"},{"key":"e_1_3_6_38_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.108.782888"},{"key":"e_1_3_6_39_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGENETICS.113.000118"},{"key":"e_1_3_6_40_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.116.004742"},{"key":"e_1_3_6_41_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.109.863076"},{"key":"e_1_3_6_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2005.09.056"},{"key":"e_1_3_6_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2009.09.069"},{"key":"e_1_3_6_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.trsl.2012.08.005"},{"key":"e_1_3_6_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2019.06.072"},{"key":"e_1_3_6_46_2","volume-title":"In: Sports Cardiology Essentials","author":"Landstrom AP","year":"2011","unstructured":"Landstrom, AP, Tester, DJ, Ackerman, MJ. Role of Genetic Testing for Sudden Death Predisposing Heart Conditions in Athletes. LawlessC, ed. In: Sports Cardiology Essentials. Springer; 2011."},{"key":"e_1_3_6_47_2","doi-asserted-by":"publisher","DOI":"10.1161\/HCG.0000000000000067"},{"key":"e_1_3_6_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/0002-8703(57)90079-0"},{"key":"e_1_3_6_49_2","doi-asserted-by":"publisher","DOI":"10.1017\/S1047951112001138"},{"key":"e_1_3_6_50_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.109.863209"},{"key":"e_1_3_6_51_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0196-17"},{"key":"e_1_3_6_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(95)90358-5"},{"key":"e_1_3_6_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(95)90359-3"},{"key":"e_1_3_6_54_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.294.23.2975"},{"key":"e_1_3_6_55_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2005.01.020"},{"key":"e_1_3_6_56_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.119.043132"},{"key":"e_1_3_6_57_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.91.5.1512"},{"key":"e_1_3_6_58_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2019.00092"},{"key":"e_1_3_6_59_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.0000020013.73106.d8"},{"key":"e_1_3_6_60_2","doi-asserted-by":"publisher","DOI":"10.1016\/0735-1097(92)90253-j"},{"key":"e_1_3_6_61_2","doi-asserted-by":"publisher","DOI":"10.14797\/mdcj-10-1-25"},{"key":"e_1_3_6_62_2","doi-asserted-by":"publisher","DOI":"10.1038\/32675"},{"key":"e_1_3_6_63_2","doi-asserted-by":"publisher","DOI":"10.1161\/hc1102.105288"},{"key":"e_1_3_6_64_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.107.703330"},{"key":"e_1_3_6_65_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI33891"},{"key":"e_1_3_6_66_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.118.035070"},{"key":"e_1_3_6_67_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.287.10.1308"},{"key":"e_1_3_6_68_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198911163212005"},{"key":"e_1_3_6_69_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2012.02.068"},{"key":"e_1_3_6_70_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0022-2828(03)00146-9"},{"key":"e_1_3_6_71_2","doi-asserted-by":"publisher","DOI":"10.1186\/1476-7120-6-62"},{"key":"e_1_3_6_72_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2009.02.075"},{"key":"e_1_3_6_73_2","doi-asserted-by":"publisher","DOI":"10.1007\/s003920050324"},{"key":"e_1_3_6_74_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2003.10.037"},{"key":"e_1_3_6_75_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.105.616490"},{"key":"e_1_3_6_76_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGEN.118.002237"},{"key":"e_1_3_6_77_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(00)02379-5"},{"key":"e_1_3_6_78_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2010.12.036"},{"key":"e_1_3_6_79_2","doi-asserted-by":"publisher","DOI":"10.1253\/circj.cj-11-0927"},{"key":"e_1_3_6_80_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGENETICS.113.000288"},{"key":"e_1_3_6_81_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2009.11.020"},{"key":"e_1_3_6_82_2","doi-asserted-by":"publisher","DOI":"10.1002\/mgg3.593"},{"key":"e_1_3_6_83_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.80.3.564"},{"key":"e_1_3_6_84_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199201093260201"},{"key":"e_1_3_6_85_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2004.11.066"},{"key":"e_1_3_6_86_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.296.15.1867"},{"key":"e_1_3_6_87_2","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.116.003450"},{"key":"e_1_3_6_88_2","doi-asserted-by":"publisher","DOI":"10.3390\/jcdd4030011"},{"key":"e_1_3_6_89_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1110186"},{"key":"e_1_3_6_90_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.119.037661"},{"key":"e_1_3_6_91_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-018-0039-z"},{"key":"e_1_3_6_92_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGEN.120.003131"},{"key":"e_1_3_6_93_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-020-0810-9"},{"key":"e_1_3_6_94_2","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2014.29"},{"key":"e_1_3_6_95_2","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.26"},{"key":"e_1_3_6_96_2","doi-asserted-by":"publisher","DOI":"10.1038\/s10038-017-0347-1"},{"key":"e_1_3_6_97_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00438-018-1431-8"},{"key":"e_1_3_6_98_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2020.04.005"},{"key":"e_1_3_6_99_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-019-0616-z"},{"key":"e_1_3_6_100_2","doi-asserted-by":"publisher","DOI":"10.1161\/HCG.0000000000000054"}],"container-title":["Circulation: Genomic and Precision Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCGEN.120.003200","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T01:12:22Z","timestamp":1715562742000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCGEN.120.003200"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8]]},"references-count":99,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2021,8]]}},"alternative-id":["10.1161\/CIRCGEN.120.003200"],"URL":"https:\/\/doi.org\/10.1161\/circgen.120.003200","relation":{},"ISSN":["2574-8300"],"issn-type":[{"value":"2574-8300","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8]]},"assertion":[{"value":"2021-08-13","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e003200"}}