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Fig. 2 | Genome Medicine

Fig. 2

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

Fig. 2

Distribution of rare variants in HCM and ExAC cohorts for 6 genes with HCM clustering. Clustering analyses identify regions enriched for disease-associated variation, and therefore within which variants have a high likelihood of pathogenicity. For six HCM genes, the location of rare missense and single amino acid inframe indel variants found in cases (all variants regardless of clinical classification) and controls are shown alongside a cartoon of the cDNA structure. Darker grey indicates higher variant density (overlapping variants not plotted separately). Regions in which variants cluster significantly in cases are shown in red, and regions with clustering in population controls (ExAC) are shown in yellow. The HCM clusters detected were: MYH7 (residues 167–931), MYBPC3 (485–502, 1248–1266), TNNI3 (141–209), TNNT2 (79–179), MYL3 (143–180) and CSRP3 (44–71). For MYH7, existing functional annotations (as described in the “Discussion” section) are superimposed: In green, key residues of the converter kinetic domain and myosin mesa surface area enriched in disease-associated variants (Homburger et al. [37]); in blue, sites of inter- and intramolecular interaction between pairs of myosin heads (Alamo et al. [38]); and in grey, regions previously identified as constrained (intolerant of variation as evidenced by depletion of protein-altering variation in population controls), with the darker shades indicating higher constraint (Samocha et al. [36]). The coordinates describe amino-acid position within the canonical protein sequence

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