Walsh, RoddyRoddyWalshLahrouchi, NajimNajimLahrouchiTadros, RafikRafikTadrosKyndt, FlorenceFlorenceKyndtGlinge, CharlotteCharlotteGlingePostema, Pieter GPieter GPostemaAmin, Ahmad SAhmad SAminNannenberg, Eline AEline ANannenbergWare, James SJames SWareWhiffin, NicolaNicolaWhiffinMazzarotto, FrancescoFrancescoMazzarottoŠkorić-Milosavljević, DorisDorisŠkorić-MilosavljevićKrijger, ChristianChristianKrijgerArbelo, ElenaElenaArbeloBabuty, DominiqueDominiqueBabutyBarajas-Martinez, HectorHectorBarajas-MartinezBeckmann, Britt MBritt MBeckmannBézieau, StéphaneStéphaneBézieauBos, J MartijnJ MartijnBosBreckpot, JeroenJeroenBreckpotCampuzano, OscarOscarCampuzanoCastelletti, SilviaSilviaCastellettiCelen, CandanCandanCelenClauss, SebastianSebastianClaussCorveleyn, AnniekAnniekCorveleynCrotti, LiaLiaCrottiDagradi, FedericaFedericaDagradide Asmundis, CarloCarlode AsmundisDenjoy, IsabelleIsabelleDenjoyDittmann, SvenSvenDittmannEllinor, Patrick TPatrick TEllinorOrtuño, Cristina GilCristina GilOrtuñoGiustetto, CarlaCarlaGiustettoGourraud, Jean-BaptisteJean-BaptisteGourraudHazeki, DaisukeDaisukeHazekiHorie, MinoruMinoruHorieIshikawa, TaisukeTaisukeIshikawaItoh, HidekiHidekiItohKaneko, YoshiakiYoshiakiKanekoKanters, Jørgen KJørgen KKantersKimoto, HirokiHirokiKimotoKotta, Maria-ChristinaMaria-ChristinaKottaKrapels, Ingrid P CIngrid P CKrapelsKurabayashi, MasahikoMasahikoKurabayashiLazarte, JulietaJulietaLazarteLeenhardt, AntoineAntoineLeenhardtLoeys, Bart LBart LLoeysLundin, CatarinaCatarinaLundinMakiyama, TakeruTakeruMakiyamaMansourati, JacquesJacquesMansouratiMartins, Raphaël PRaphaël PMartinsMazzanti, AndreaAndreaMazzantiMörner, StellanStellanMörnerNapolitano, CarloCarloNapolitanoOhkubo, KimieKimieOhkuboPapadakis, MichaelMichaelPapadakisRudic, BorisBorisRudicMolina, Maria SabaterMaria SabaterMolinaSacher, FrédéricFrédéricSacherSahin, HaticeHaticeSahinSarquella-Brugada, GeorgiaGeorgiaSarquella-BrugadaSebastiano, ReginaReginaSebastianoSharma, SanjaySanjaySharmaSheppard, Mary NMary NSheppardShimamoto, KeikoKeikoShimamotoShoemaker, M BenjaminM BenjaminShoemakerStallmeyer, BirgitBirgitStallmeyerSteinfurt, JohannesJohannesSteinfurtTanaka, YujiYujiTanakaTester, David JDavid JTesterUsuda, KeisukeKeisukeUsudavan der Zwaag, Paul APaul Avan der ZwaagVan Dooren, SoniaSoniaVan DoorenVan Laer, LutLutVan LaerWinbo, AnnikaAnnikaWinboWinkel, Bo GBo GWinkelYamagata, KenichiroKenichiroYamagataZumhagen, SvenSvenZumhagenVolders, Paul G APaul G AVoldersLubitz, Steven ASteven ALubitzAntzelevitch, CharlesCharlesAntzelevitchPlatonov, Pyotr GPyotr GPlatonovOdening, Katja ElisabethKatja ElisabethOdeningRoden, Dan MDan MRodenRoberts, Jason DJason DRobertsSkinner, Jonathan RJonathan RSkinnerTfelt-Hansen, JacobJacobTfelt-Hansenvan den Berg, Maarten PMaarten Pvan den BergOlesen, Morten SMorten SOlesenLambiase, Pier DPier DLambiaseBorggrefe, MartinMartinBorggrefeHayashi, KenshiKenshiHayashiRydberg, AnnikaAnnikaRydbergNakajima, TadashiTadashiNakajimaYoshinaga, MasaoMasaoYoshinagaSaenen, Johan BJohan BSaenenKääb, StefanStefanKääbBrugada, PedroPedroBrugadaRobyns, TomasTomasRobynsGiachino, Daniela FDaniela FGiachinoAckerman, Michael JMichael JAckermanBrugada, RamonRamonBrugadaBrugada, JosepJosepBrugadaGimeno, Juan RJuan RGimenoHasdemir, CanCanHasdemirGuicheney, PascalePascaleGuicheneyPriori, Silvia GSilvia GPrioriSchulze-Bahr, EricEricSchulze-BahrMakita, NaomasaNaomasaMakitaSchwartz, Peter JPeter JSchwartzShimizu, WataruWataruShimizuAiba, TakeshiTakeshiAibaSchott, Jean-JacquesJean-JacquesSchottRedon, RichardRichardRedonOhno, SeikoSeikoOhnoProbst, VincentVincentProbstBehr, Elijah RElijah RBehrBarc, JulienJulienBarcBezzina, Connie RConnie RBezzina2024-09-022024-09-022021-01https://boris-portal.unibe.ch/handle/20.500.12422/37833PURPOSE Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate. METHODS We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants. RESULTS Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 × 10-18) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 × 10-13). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency. CONCLUSION Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing.enACMG/AMP guidelines Brugada LQTS variant interpretation600 - Technology::610 - Medicine & healtharticle10.7892/boris.1478313289326710.1038/s41436-020-00946-5