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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
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Genome Medicine

ISSN: 1756-994X

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