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Fig. 4 | Genome Medicine

Fig. 4

From: Quantitative approaches to variant classification increase the yield and precision of genetic testing in Mendelian diseases: the case of hypertrophic cardiomyopathy

Fig. 4

Effect of EF-based approach to variant classification in HCM cohorts. a Proportion of cases from the OMGL/LMM HCM cohorts with variants in 8 sarcomeric genes (only rare variants, ExAC filtering frequency < 4 × 10−5, are shown, excluding non-essential splice site variants). Coloured shading represents the clinical classification of the original diagnostic laboratory (OMGL and LMM), and, for variants originally classified as VUS, the proportion that could be reclassified as Likely Pathogenic based on occurrence within a gene or region with EF ≥ 0.95. Eighty-nine variants in 123 cases for MYH7, 12 variants in 27 cases for MYBPC3, 18 variants in 34 cases for TNNI3, 15 variants in 18 cases for TNNT2 and 22 variants in 33 cases for TPM1 would be upgraded based on this analysis. b Proportion of cases in a prospective HCM cohort classified as actionable based on application of fixed and automatable ACMG/AMP rules, alongside the addition of manual curation of published evidence and the proposed EF-calibrated PM1 rules. Thirty-one extra cases (4.5%) are upgraded with EF-based rules compared to just 4 (0.6%) with manual curation. c Comparison of indexed LV mass in cases with pathogenic variants, VUS in high EF (≥ 0.95) regions, and VUS in low EF regions (< 0.95) in MYH7/MYBPC3 as well as genotype-negative cases, from the prospective HCM cohort. The clinical phenotype of individuals with VUS at locations anticipated to be pathogenic is indistinguishable from known pathogenic/likely pathogenic variants, while individuals with VUS in other regions have a clinical phenotype more similar to individuals without a sarcomere variant. d Kaplan-Meier survival curve for the overall composite endpoint (including mortality, ventricular arrhythmia and heart failure composites) of the SHaRe cardiomyopathy registry stratified by genotype (HCM cases with pathogenic variants, VUS in high EF region (≥ 0.95), VUS in lower EF regions (< 0.95), and genotype-negative cases)

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