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Table 1 Etiological fractions and odds ratios for established HCM genes

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

Gene Transcript Number of cases Case frequency (variants/total) ExAC frequency (variants/total) p value Odds ratio (OR) Etiological fraction (EF)
Non-truncating variants
 MYH7 ENST00000355349 6112 13.89% (849/6112) 1.11% (672/60,469) < 0.0001 14.4 (12.9–15.9) 0.930 (0.923–0.938)
 MYBPC3 ENST00000545968 6179 9.35% (578/6179) 1.21% (555/45,794) < 0.0001 8.4 (7.5–9.5) 0.881 (0.868–0.895)
 TNNT2 ENST00000367318 6103 1.69% (103/6103) 0.15% (86/57,018) < 0.0001 11.4 (8.5–15.2) 0.912 (0.889–0.935)
 TNNI3 ENST00000344887 6047 2.10% (127/6047) 0.15% (79/52,607) < 0.0001 14.3 (10.8–18.9) 0.930 (0.912–0.948)
 TPM1 ENST00000403994 4447 1.44% (64/4447) 0.07% (42/58,642) < 0.0001 20.4 (13.8–30.1) 0.951 (0.933–0.969)
 MYL2 ENST00000228841 4185 1.03% (43/4185) 0.11% (69/60,521) < 0.0001 9.1 (6.2–13.3) 0.890 (0.851–0.930)
 MYL3 ENST00000395869 4185 0.84% (35/4185) 0.14% (85/60,605) < 0.0001 6.0 (4.0–8.9) 0.833 (0.772–0.895)
 ACTC1 ENST00000290378 4185 0.53% (22/4185) 0.06% (37/60,198) < 0.0001 8.6 (5.1–14.6) 0.884 (0.826–0.941)
 PLN ENST00000357525 5440 0.17% (9/5440) 0.02% (15/60,475) < 0.0001 6.7 (2.9–15.3) 0.850 (0.737–0.964)
 CSRP3 ENST00000533783 4866 0.62% (30/4866) 0.19% (115/60,647) < 0.0001 3.3 (2.2–4.9) 0.694 (0.579–0.808)
 FHL1 ENST00000370690 2061 0.78% (16/2061) 0.09% (53/60,278) < 0.0001 8.9 (5.1–15.6) 0.888 (0.826–0.949)
 TNNC1 ENST00000232975 3335 0.24% (8/3335) 0.06% (33/59,192) 0.0013 4.3 (2.0–9.3) 0.768 (0.598–0.938)
 FLNC ENST00000325888 448 3.79% (17/448) 2.15% (1225/56,897) 0.0314 1.8 (1.1–2.9) 0.442 (0.172–0.712)
 FHOD3 ENST00000590592 3189 2.26% (72/3189) 1.20% (683/57,035) < 0.0001 1.9 (1.5–2.4) 0.475 (0.353–0.597)
Truncating variants
 MYBPC3 ENST00000545968 6179 9.16% (566/6179) 0.09% (40/45,794) < 0.0001 115.3 (83.6–159.1) 0.991 (0.988–0.995)
 TNNT2 ENST00000367318 6103 0.18% (11/6103) 0.03% (17/57,018) < 0.0001 6.1 (2.8–12.9) 0.835 (0.722–0.948)
 TNNI3 ENST00000344887 6047 0.08% (5/6047) 0.01% (5/52,607) 0.0019 8.7 (2.5–30.1) 0.885 (0.757–1.013)
 PLN ENST00000357525 5440 0.17% (9/5440) 0.01% (4/60,475) < 0.0001 25.1 (7.7–81.4) 0.960 (0.917–1.003)
 CSRP3 ENST00000533783 4866 0.14% (7/4866) 0.02% (14/60,647) 0.0006 6.2 (2.5–15.5) 0.840 (0.705–0.974)
 FHL1 ENST00000370690 2061 0.15% (3/2061) 0.00% (0/60,278) < 0.0001 205.0 (10.6–3969.8) 0.995 (0.981–1.009)
  1. Displayed are the cumulative frequency of rare variants (rare defined by ExAC filtering allele frequency < 4 × 10−5 [22]), Fisher’s exact test p values and estimates of odds ratio and etiological fraction (with 95% confidence intervals) for non-truncating and truncating variants in HCM genes. The etiological fraction can be interpreted as an estimate of the probability that a rare variant, found in an individual with HCM, is causative. This suggests that the majority of variants are pathogenic when detected in cases, and for some genes, the probability that an individual variant is pathogenic is > 0.9, before considering variant-specific segregation of functional data. Only variant classes with a significant excess of variants in case cohorts over ExAC are displayed