Critical assessment of secondary findings in genes linked to primary arrhythmia syndromes

Figures

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  Figure 1. Flow chart of variant filtering steps for identification of pathogenic variants in the actionable genes RYR2, KCNQ1, KCNH2, and SCN5A. 6,381 next‐generation sequencing (NGS) data were analyzed for pathogenic variants in RYR2, KCNQ1, KCNH2, and SCN5A. Variants were filtered based on genotype quality, coverage and allele frequency. The variants were considered benign when the minor allele frequency (MAF) was >0.01. Number and type of variants after the filtering step was listed as codon insertion/deletion (codon ins/del), loss of function (LoF) variants and missense variants. LoF variants include frameshift, stop‐gain, start‐loss, and splice‐site variants. Number of variants classified as pathogenic (class 4, class 5 according to the ACMG guidelines and disease causing mutations (DM)) in at least one of the databases Human Gene Mutation Database (HGMD), public archive of interpretations of clinically relevant variants (ClinVar), Leiden Open‐source Variant Database (LOVD), or by Medical Genetics Center (MGZ)‐curators were listed

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  Figure 2. Variant classification of secondary findings in RYR2, KCNQ1, KCNH2, and SCN5A. Data from 6381 next‐generation sequencing (NGS) runs were analyzed for pathogenic variants in RYR2, KCNQ1, KCNH2, and SCN5A. Variants were selected for further interpretation if they were classified as pathogenic in at least one of the databases Human Gene Mutation Database (HGMD), ClinVar (public archive of interpretations of clinically relevant variants), Leiden Open‐source Variant Database (LOVD), or by Medical Genetics Center (MGZ)‐curators (MGZ; class 4 and class 5 according to the ACMG guidelines or disease causing mutations, DM). Red bars indicate the percentage of pathogenic variants, blue bars indicate the percentage of variants of unknown significance (class 3 according to the ACMG guidelines or disease causing? (DM?)), green bars indicate benign variants (class 1 and class 2 according to the ACMG guidelines), purple bars indicate conflicting data of variant interpretation by different submitters. HGMD listed 86 variants (95%), ClinVar 18 variants (20%), LOVD 11 variants (12%), and MGZ classified 26 variants (29%) as pathogenic. ClinVar listed 29% conflicting data