TABLE 1.

Spectrum of Genetic Variants in the Human Genome

Category	Description	Relevance to HCM
Nonsynonymous SNVs (nsSNVs)	Change amino acid sequence Missense variants are most common A small fraction is non-sense ~ 12,000 in each genome	Most common type of mutations (PVs) identified in HCM
Insertion/deletion variants (Indels)	Second most common variants in the genome ~ 100,000 to 1,000,000 in each genome Involve 1 to 50 nucleotides ~ 110 indel in each genome maintain coding frame ~ 40 indels in each genome result in a frame shift	Uncommon causes of HCM Mostly identified in the MYBPC3 gene In-frame indels are benign but rate cause disease (such as cystic fibrosis)
Splice junction variants	Could lead to alternative splicing by affecting canonical donor or acceptor site or their vicinity Could introduce frame shift and lead to haploinsufficiency	Uncommon causes of HCM Mostly identified in the MYBPC3 gene Responsible for ~ 10% of human diseases
Synonymous SNVs (silent variants) (synSNVs)	No change in amino acid sequence Could affect transcriptional and translational efficiency Could introduce cryptic splice ~ 12,000 in each genome	Unclear role in HCM
Regulatory variants	Variants in the 5’ regulatory region could affect transcriptions Variants in the 3’ regulatory region could affect mRNA stability and microRNA binding	Unclear role in HCM
Intronic and intergenic variants	The vast majority of the variants in the human genome Might affect enhances Might introduce cryptic splice sites	Unclear role in HCM
Structural variants (SVs)	Defined as large indels and genomic rearrangements Involve > 50 nucleotides, typically more than 1,000, and occasionally > million nucleotides Could affect copy number of the involved genes and hence, their expression levels Difficult to identify by short-read sequencing	Unclear role in HCM

Abbreviations:

SNVs: Single nucleotide polymorphism; HCM: Hypertrophic cardiomyopathy; PV: Pathogenic variant s; MYBPC3: Myosin binding protein C3; Indel: insertion/deletion