Fig. 2

Validating CardiacG2P. Two generic variant prioritisation pipelines (pipelines 1 and 2) were compared to CardiacG2P (pipeline 3). All 3 pipelines interrogate the same gene list which includes 21 HCM and 12 DCM genes. Pipeline 1: filtered rare (gnomAD global allele frequency (AF) <0.0001) AND protein-altering variants. Pipeline 2: filtered rare (AF <0.0001) AND ((high impact variants (e.g. stop gained, frameshift) AND high confidence by LOFTEE (VEP plugin) LoF variants) OR ClinVar P/LP variants). CardiacG2P (pipeline 3): filtered rare variants (AF <0.0001) and incorporates allelic requirement, variant consequence, and gene-specific annotations of a restricted repertoire of pathogenic alleles appropriate for the disease under interrogation—e.g. restricted variant classes, specific variants, or restricted regions of the protein. Set 1: contains 285 unique variants identified and classified as P/LP for HCM or DCM by a specialist NHS cardiovascular genetics lab. A VCF file with these variants was created, annotated by VEP, and filtered according to the 3 pipelines. Sensitivity (number of P/LP variants retained) was assessed. Set 2a: is a merged VCF file with SNVs and indels from 200 patients with HCM or DCM. Set2b: is a merged VCF file with SNVs and indels from 200 healthy volunteers. Set2a and 2b were separately annotated by VEP and filtered according to the 3 pipelines. Positive rate (the number of variants retained for further analysis) was assessed. AF, allele frequency; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; indels, insertion or deletion variants; LoF, loss of function; P/LP, pathogenic/likely pathogenic; SNVs, single nucleotide variants; VCF, variant call format; VEP, variant effect predictor