TNNI3 non-truncating variants in HCM cohorts

The table below lists the 63 rare (MAF<0.0001 in ExAC) non-truncating TNNI3 variants identified in a cohort of 2912 HCM patients. When this rare variant frequency of 0.02163 is compared with a background population rate of 0.00186, there is a statistically significant case excess of 0.01977 (p<0.0001), which suggests that approximately 57 of these variants may be pathogenic.

Variant Type:      All protein-altering variants     -     Truncating variants     -     Non-Truncating variants
Source:      Combined (OMGL + LMM)     -     OMGL     -     LMM

No. Variant (CDS) Variant (Protein) Variant Type Cases (2912)LMM class ExAC frequency
1. c.470C>T p.A157Vmissense 8Pathogenic0.000000
2. c.485G>A p.R162Qmissense 8Likely Pathogenic0.000024
3. c.422G>A p.R141Qmissense 5Likely Pathogenic0.000000
4. c.434G>A p.R145Qmissense 4Likely Pathogenic0.000024
5. c.611G>A p.R204Hmissense 3Likely Pathogenic0.000000
6. c.428C>A p.T143Nmissense 3VUS0.000024
7. c.557G>A p.R186Qmissense 3Pathogenic0.000000
8. c.433C>T p.R145Wmissense 3Pathogenic0.000008
9. c.586G>A p.D196Nmissense 2VUS favour pathogenic0.000008
10. c.610C>T p.R204Cmissense 2VUS favour pathogenic0.000000
11. c.575G>A p.R192Hmissense 2Likely Pathogenic0.000000
12. c.236G>T p.R79Lmissense 2VUS0.000046
13. c.509G>A p.R170Qmissense 2Pathogenic0.000000
14. c.484C>T p.R162Wmissense 2VUS0.000033
15. c.602T>C p.M201Tmissense 1Likely Pathogenic0.000000
16. c.368C>T p.T123Mmissense 1VUS0.000025
17. c.568G>T p.D190Ymissense 1Likely Pathogenic0.000000
18. c.431T>C p.L144Pmissense 1Pathogenic0.000000
19. c.433C>G p.R145Gmissense 1Pathogenic0.000000
20. c.592C>G p.L198Vmissense 1VUS favour pathogenic0.000000
21. c.575G>T p.R192Lmissense 1Likely Pathogenic0.000000
22. c.497C>T p.S166Fmissense 1VUS favour pathogenic0.000008
23. c.625G>A p.E209Kmissense 1VUS favour pathogenic0.000000
24. c.485G>C p.R162Pmissense 1Likely Pathogenic0.000000
25. c.532_534delAAG inframe 1Pathogenic0.000000
26. c.579G>C p.K193Nmissense 1VUS favour pathogenic0.000000
27. c.526G>A p.V176Mmissense 1VUS favour pathogenic0.000000
28. c.167T>C p.I56Tmissense 1VUS favour pathogenic0.000024


1. Roddy Walsh, Kate L. Thomson, James S. Ware, Birgit H. Funke, Jessica Woodley, Karen J. McGuire, Francesco Mazzarotto, Edward Blair, Anneke Seller, Jenny C. Taylor, Eric V. Minikel, Exome Aggregation Consortium, Daniel G. MacArthur, Martin Farrall, Stuart A. Cook and Hugh Watkins. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2016 doi:10.1038/gim.2016.90.

2. Alfares AA, Kelly MA, McDermott G, Funke BH, Lebo MS, Baxter SB, Shen J, McLaughlin HM, Clark EH, Babb LJ, Cox SW, DePalma SR, Ho CY, Seidman JG, Seidman CE, Rehm HL. Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity. Genet Med. 2015 Nov;17(11):880-8.