Key result
Three intronic MYBPC3 variants cause in vitro splicing errors, prompting reclassification as likely pathogenic.
Why the study?
While canonical splice site variants in MYBPC3 are a well-characterised cause of HCM, work has only recently begun to investigate the pathogenicity of more deeply intronic variants.
Do intronic splice-affecting variants in MYBPC3 result in splicing errors in patients with hypertrophic cardiomyopathy?
Case Report (n=3)
Do intronic splice-affecting variants in MYBPC3 result in splicing errors in patients with hypertrophic cardiomyopathy?
Functional assessment of intronic MYBPC3 variants demonstrates splicing errors, leading to the reclassification of variants of uncertain significance to likely pathogenic in HCM.
May support reclassification of these MYBPC3 variants in HCM; leaves open need for clinical validation studies.
Genetic variants in MYBPC3 are one of the most common causes of hypertrophic cardiomyopathy (HCM). While variants in MYBPC3 affecting canonical splice site dinucleotides are a well-characterised cause of HCM, only recently has work begun to investigate the pathogenicity of more deeply intronic variants. Here, we present three patients with HCM and intronic splice-affecting MYBPC3 variants and analyse the impact of variants on splicing using in vitro minigene assays. We show that the three variants, a novel c.927-8G>A variant and the previously reported c.1624+4A>T and c.3815-10T>G variants, result in MYBPC3 splicing errors. Analysis of blood-derived patient RNA for the c.3815-10T>G variant revealed only wild type spliced product, indicating that mis-spliced transcripts from the mutant allele are degraded. These data indicate that the c.927-8G>A variant of uncertain significance and likely benign c.3815-10T>G should be reclassified as likely pathogenic. Furthermore, we find shortcomings in commonly applied bioinformatics strategies to prioritise variants impacting MYBPC3 splicing and re-emphasise the need for functional assessment of variants of uncertain significance in diagnostic testing.
No takes yet. Share an insight, caveat, or question.
Wood et al. (2021) conducted a case report in Hypertrophic cardiomyopathy (HCM) (n=3). MYBPC3 intronic splice-affecting variants (c.927-8G>A, c.1624+4A>T, c.3815-10T>G) was evaluated on Impact of variants on splicing (MYBPC3 splicing errors). Three intronic MYBPC3 variants (c.927-8G>A, c.1624+4A>T, and c.3815-10T>G) resulted in splicing errors in vitro, indicating they should be reclassified as likely pathogenic.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: