TABLE2.

Categorization of the Genetic Variant for Clinical Applications in HCM

Category	Definition	Characteristics
PVs	Variants for which there is a strong genetic evidence for their involvement in the pathogenesis of HCM	PVs are predicted to distort structure and function of the encoded proteins, often leading to premature truncation of the protein and haplo-insufficiency Frameshift variants, such as indels and splice junction variants Variants leading to gain or loss of a stop codon Missense variants with a high CADD score Rare in the general population Typically involve genes that are intolerant to LoF variants
LPVs	As for PVs, except that genetic evidence for their involvement in the pathogenesis of HCM is less robust	LPVs have characteristics similar to those of the PVs Typically they involve genes that are partially intolerant to LoF variants
Functional variants with undefined clinical significance	Variants affect gene expression and/or protein function but are not associated with a clinical phenotype	Relatively common in the genome Functional effects at the mRNA and/or protein levels Involve genes that are tolerant to LoF variants
Variants with unknown significance	Undefined functional or clinical significance	Common in the genome Often located in intergenic regions or introns
Likely benign variants	These variants are not expected to cause discernible phenotypic effects. They might have modest effects on gene expression but are not related to HCM	Common in the general population Are not predicted to exert functional or clinical effects
Benign variants	Variants with no discernible functional, biological, or clinical effects	Common in the general population These variants are expected to be inconsequential at the functional and clinical levels

Abbreviations:

PVs: Pathogenic variants; LPVs: Likely pathogenic variants; LoF: Predicted loss of function; CADD: Combined Annotated Dependent Depletion, which is a score calculated upon integration of more than 60 genomic features of single nucleotide variants and indels.