Pathogenic Intronic Splice-Affecting Variants in MYBPC3 in Three Patients with Hypertrophic Cardiomyopathy

Genetic variants in MYBPC3 are one of the most common causes hypertrophic cardiomyopathy (HCM). While affecting canonical splice site dinucleotides a well-characterised cause HCM, only recently has work begun to investigate pathogenicity more deeply intronic variants. Here, we present three patients with HCM and splice-affecting analyse impact on splicing using vitro minigene assays. We show that variants, novel c.927-8G>A variant previously reported c.1624+4A>T c.3815-10T>G result errors. Analysis blood-derived patient RNA for revealed wild type spliced product, indicating mis-spliced transcripts from mutant allele degraded. These data indicate uncertain significance likely benign should be reclassified as pathogenic. Furthermore, find shortcomings commonly applied bioinformatics strategies prioritise impacting re-emphasise need functional assessment diagnostic testing.