Josephs, Katherine SKatherine SJosephsRoberts, Angharad MAngharad MRobertsTheotokis, PantazisPantazisTheotokisWalsh, RoddyRoddyWalshOstrowski, Philip JPhilip JOstrowskiEdwards, MatthewMatthewEdwardsFleming, AndrewAndrewFlemingThaxton, CourtneyCourtneyThaxtonRoberts, Jason DJason DRobertsCare, MelanieMelanieCareZareba, WojciechWojciechZarebaAdler, ArnonArnonAdlerSturm, Amy CAmy CSturmTadros, RafikRafikTadrosNovelli, ValeriaValeriaNovelliOwens, EmmaEmmaOwensBronicki, LucasLucasBronickiJarinova, OlgaOlgaJarinovaCallewaert, BertBertCallewaertPeters, StaceyStaceyPetersLumbers, TomTomLumbersJordan, ElizabethElizabethJordanAsatryan, BabkenBabkenAsatryan0000-0002-0050-5717Krishnan, NeeshaNeeshaKrishnanHershberger, Ray ERay EHershbergerChahal, C Anwar AC Anwar AChahalLandstrom, Andrew PAndrew PLandstromJames, CynthiaCynthiaJamesMcNally, Elizabeth MElizabeth MMcNallyJudge, Daniel PDaniel PJudgevan Tintelen, PeterPetervan TintelenWilde, ArthurArthurWildeGollob, MichaelMichaelGollobIngles, JodieJodieInglesWare, James SJames SWare2024-10-252024-10-252023-10-23https://boris-portal.unibe.ch/handle/20.500.12422/170839BACKGROUND As the availability of genomic testing grows, variant interpretation will increasingly be performed by genomic generalists, rather than domain-specific experts. Demand is rising for laboratories to accurately classify variants in inherited cardiac condition (ICC) genes, including secondary findings. METHODS We analyse evidence for inheritance patterns, allelic requirement, disease mechanism and disease-relevant variant classes for 65 ClinGen-curated ICC gene-disease pairs. We present this information for the first time in a structured dataset, CardiacG2P, and assess application in genomic variant filtering. RESULTS For 36/65 gene-disease pairs, loss of function is not an established disease mechanism, and protein truncating variants are not known to be pathogenic. Using the CardiacG2P dataset as an initial variant filter allows for efficient variant prioritisation whilst maintaining a high sensitivity for retaining pathogenic variants compared with two other variant filtering approaches. CONCLUSIONS Access to evidence-based structured data representing disease mechanism and allelic requirement aids variant filtering and analysis and is a pre-requisite for scalable genomic testing.enAllelic requirement Disease mechanism Gene curation Genomic variant filtering Inheritance Inherited cardiac conditions Variant classification Variant interpretation600 - Technology::610 - Medicine & healtharticle10.48350/1873973787264010.1186/s13073-023-01246-8