Aisha Furqan1, Patricia Arscott1, Francesca Girolami1, Allison L Cirino1, Michelle Michels1, Sharlene M Day1, Iacopo Olivotto1, Carolyn Y Ho1, Euan Ashley1, Eric M Green1, Colleen Caleshu2. 1. From the California Department of Biological Sciences, State University, Stanislaus, Turlock, CA (A.F.); Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI (P.A., S.M.D.); Genetics Unit, Careggi University Hospital, Florence, Italy (F.G.); Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (A.L.C., C.Y.H.); Department of Cardiology, Thoraxcenter, Erasmus Medical Center, Rotterdam, The Netherlands (M.M.); Referral Center for Myocardial Diseases, Azienda Ospedaliera Universitaria Careggi, Florence, Italy (I.O.); Stanford Center for Inherited Cardiovascular Disease, Stanford Medical Center, CA (E.A., C.C.); Division of Cardiovascular Medicine (E.A.) and Division of Medical Genetics (C.C.), Stanford University Medical Center, Stanford, CA; and Translational Research, MyoKardia Inc., South San Francisco, CA (E.M.G.). 2. From the California Department of Biological Sciences, State University, Stanislaus, Turlock, CA (A.F.); Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI (P.A., S.M.D.); Genetics Unit, Careggi University Hospital, Florence, Italy (F.G.); Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (A.L.C., C.Y.H.); Department of Cardiology, Thoraxcenter, Erasmus Medical Center, Rotterdam, The Netherlands (M.M.); Referral Center for Myocardial Diseases, Azienda Ospedaliera Universitaria Careggi, Florence, Italy (I.O.); Stanford Center for Inherited Cardiovascular Disease, Stanford Medical Center, CA (E.A., C.C.); Division of Cardiovascular Medicine (E.A.) and Division of Medical Genetics (C.C.), Stanford University Medical Center, Stanford, CA; and Translational Research, MyoKardia Inc., South San Francisco, CA (E.M.G.). ccaleshu@stanfordhealthcare.org.
Abstract
BACKGROUND: Clinically impactful differences in the interpretation of genetic test results occur between laboratories and clinicians. To improve the classification of variants, a better understanding of why discrepancies occur and how they can be reduced is needed. METHODS AND RESULTS: We examined the frequency, causes, and resolution of discordant variant classifications in the Sarcomeric Human Cardiomyopathy Registry (SHaRe), a consortium of international centers with expertise in the clinical management and genetic architecture of hypertrophic cardiomyopathy. Of the 112 variants present in patients at >1 center, 23 had discordant classifications among centers (20.5%; Fleiss κ, 0.54). Discordance was more than twice as frequent among clinical laboratories in ClinVar, a public archive of variant classifications (315/695 variants; 45.2%; Fleiss κ, 0.30; P<0.001). Discordance in SHaRe most frequently occurred because hypertrophic cardiomyopathy centers had access to different privately held data when making their classifications (75.0%). Centers reassessed their classifications based on a comprehensive and current data summary, leading to reclassifications that reduced the discordance rate from 20.5% to 10.7%. Different interpretations of rarity and co-occurrence with pathogenic variants contributed to residual discordance. CONCLUSIONS: Discordance in variant classification among hypertrophic cardiomyopathy centers is largely attributable to privately held data. Some discrepancies are caused by differences in expert assessment of conflicting data. Discordance was markedly lower among centers specialized in hypertrophic cardiomyopathy than among clinical laboratories, suggesting that optimal genetic test interpretation occurs in the context of clinical care delivered by specialized centers with both clinical and genetics expertise.
BACKGROUND: Clinically impactful differences in the interpretation of genetic test results occur between laboratories and clinicians. To improve the classification of variants, a better understanding of why discrepancies occur and how they can be reduced is needed. METHODS AND RESULTS: We examined the frequency, causes, and resolution of discordant variant classifications in the Sarcomeric HumanCardiomyopathy Registry (SHaRe), a consortium of international centers with expertise in the clinical management and genetic architecture of hypertrophic cardiomyopathy. Of the 112 variants present in patients at >1 center, 23 had discordant classifications among centers (20.5%; Fleiss κ, 0.54). Discordance was more than twice as frequent among clinical laboratories in ClinVar, a public archive of variant classifications (315/695 variants; 45.2%; Fleiss κ, 0.30; P<0.001). Discordance in SHaRe most frequently occurred because hypertrophic cardiomyopathy centers had access to different privately held data when making their classifications (75.0%). Centers reassessed their classifications based on a comprehensive and current data summary, leading to reclassifications that reduced the discordance rate from 20.5% to 10.7%. Different interpretations of rarity and co-occurrence with pathogenic variants contributed to residual discordance. CONCLUSIONS: Discordance in variant classification among hypertrophic cardiomyopathy centers is largely attributable to privately held data. Some discrepancies are caused by differences in expert assessment of conflicting data. Discordance was markedly lower among centers specialized in hypertrophic cardiomyopathy than among clinical laboratories, suggesting that optimal genetic test interpretation occurs in the context of clinical care delivered by specialized centers with both clinical and genetics expertise.
Authors: Laura M Amendola; Kathleen Muenzen; Leslie G Biesecker; Kevin M Bowling; Greg M Cooper; Michael O Dorschner; Catherine Driscoll; Ann Katherine M Foreman; Katie Golden-Grant; John M Greally; Lucia Hindorff; Dona Kanavy; Vaidehi Jobanputra; Jennifer J Johnston; Eimear E Kenny; Shannon McNulty; Priyanka Murali; Jeffrey Ou; Bradford C Powell; Heidi L Rehm; Bradley Rolf; Tamara S Roman; Jessica Van Ziffle; Saurav Guha; Avinash Abhyankar; David Crosslin; Eric Venner; Bo Yuan; Hana Zouk; Gail P Jarvik Journal: Am J Hum Genet Date: 2020-10-26 Impact factor: 11.025
Authors: Edgar A Rivera-Muñoz; Laura V Milko; Steven M Harrison; Danielle R Azzariti; C Lisa Kurtz; Kristy Lee; Jessica L Mester; Meredith A Weaver; Erin Currey; William Craigen; Charis Eng; Birgit Funke; Madhuri Hegde; Ray E Hershberger; Rong Mao; Robert D Steiner; Lisa M Vincent; Christa L Martin; Sharon E Plon; Erin Ramos; Heidi L Rehm; Michael Watson; Jonathan S Berg Journal: Hum Mutat Date: 2018-11 Impact factor: 4.878
Authors: Steven M Harrison; Jill S Dolinksy; Wenjie Chen; Christin D Collins; Soma Das; Joshua L Deignan; Kathryn B Garber; John Garcia; Olga Jarinova; Amy E Knight Johnson; Juha W Koskenvuo; Hane Lee; Rong Mao; Rebecca Mar-Heyming; Andrew S McFaddin; Krista Moyer; Narasimhan Nagan; Stefan Rentas; Avni B Santani; Eija H Seppälä; Brian H Shirts; Timothy Tidwell; Scott Topper; Lisa M Vincent; Kathy Vinette; Heidi L Rehm Journal: Hum Mutat Date: 2018-11 Impact factor: 4.878
Authors: Martin K Stiles; Arthur A M Wilde; Dominic J Abrams; Michael J Ackerman; Christine M Albert; Elijah R Behr; Sumeet S Chugh; Martina C Cornel; Karen Gardner; Jodie Ingles; Cynthia A James; Jyh-Ming Jimmy Juang; Stefan Kääb; Elizabeth S Kaufman; Andrew D Krahn; Steven A Lubitz; Heather MacLeod; Carlos A Morillo; Koonlawee Nademanee; Vincent Probst; Elizabeth V Saarel; Luciana Sacilotto; Christopher Semsarian; Mary N Sheppard; Wataru Shimizu; Jonathan R Skinner; Jacob Tfelt-Hansen; Dao Wu Wang Journal: Heart Rhythm Date: 2020-10-19 Impact factor: 6.343
Authors: Martin K Stiles; Arthur A M Wilde; Dominic J Abrams; Michael J Ackerman; Christine M Albert; Elijah R Behr; Sumeet S Chugh; Martina C Cornel; Karen Gardner; Jodie Ingles; Cynthia A James; Jyh-Ming Jimmy Juang; Stefan Kääb; Elizabeth S Kaufman; Andrew D Krahn; Steven A Lubitz; Heather MacLeod; Carlos A Morillo; Koonlawee Nademanee; Vincent Probst; Elizabeth V Saarel; Luciana Sacilotto; Christopher Semsarian; Mary N Sheppard; Wataru Shimizu; Jonathan R Skinner; Jacob Tfelt-Hansen; Dao Wu Wang Journal: J Arrhythm Date: 2021-04-08
Authors: Nicholas A Marston; Larry Han; Iacopo Olivotto; Sharlene M Day; Euan A Ashley; Michelle Michels; Alexandre C Pereira; Jodie Ingles; Christopher Semsarian; Daniel Jacoby; Steven D Colan; Joseph W Rossano; Samuel G Wittekind; James S Ware; Sara Saberi; Adam S Helms; Carolyn Y Ho Journal: Eur Heart J Date: 2021-05-21 Impact factor: 29.983
Authors: Austin Bland; Elizabeth A Harrington; Kyla Dunn; Mitchel Pariani; Julia C K Platt; Megan E Grove; Colleen Caleshu Journal: Genet Med Date: 2017-12-14 Impact factor: 8.822