TNNI3 variants in HCM cohorts


The table below lists the 135 rare (MAF<0.0001 in ExAC) protein-altering TNNI3 variants identified in a cohort of 6047 HCM patients (3135 patients from OMGL, 2912 patients from LMM). When this rare variant frequency of 0.02233 is compared with a background population rate of 0.00228, there is a statistically significant case excess of 0.02005 (p<0.0001), which suggests that approximately 122 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 (6047)OMGL classLMM class ExAC frequency
1. c.433C>T p.R145Wmissense 13Pathogenic (10)Pathogenic (3)0.000008
2. c.485G>A p.R162Qmissense 12VUS (4)Likely Pathogenic (8)0.000024
3. c.470C>T p.A157Vmissense 11Likely Pathogenic (3)Pathogenic (8)0.000000
4. c.422G>A p.R141Qmissense 11Likely Pathogenic (6)Likely Pathogenic (5)0.000000
5. c.484C>T p.R162Wmissense 9VUS (7)VUS (2)0.000033
6. c.586G>A p.D196Nmissense 6Likely Pathogenic (4)VUS favour pathogenic (2)0.000008
7. c.557G>A p.R186Qmissense 5Pathogenic (2)Pathogenic (3)0.000000
8. c.611G>A p.R204Hmissense 4Likely Pathogenic (1)Likely Pathogenic (3)0.000000
9. c.434G>A p.R145Qmissense 4Likely Pathogenic (4)0.000024
10. c.407G>A p.R136Qmissense 3Likely Pathogenic (3)0.000008
11. c.428C>A p.T143Nmissense 3VUS (3)0.000024
12. c.433C>G p.R145Gmissense 3Pathogenic (2)Pathogenic (1)0.000000
13. c.575G>A p.R192Hmissense 2Likely Pathogenic (2)0.000000
14. c.596G>A p.S199Nmissense 2Likely Pathogenic (2)0.000000
15. c.236G>T p.R79Lmissense 2VUS (2)0.000046
16. c.509G>A p.R170Qmissense 2Pathogenic (2)0.000000
17. c.602T>C p.M201Tmissense 2Likely Pathogenic (1)Likely Pathogenic (1)0.000000
18. c.610C>T p.R204Cmissense 2VUS favour pathogenic (2)0.000000
19. c.625G>A p.E209Kmissense 2VUS (1)VUS favour pathogenic (1)0.000000
20. c.538del p.Asp180Thrfs*19frameshift 2Pathogenic (2)0.000000
21. c.431T>C p.L144Pmissense 2Likely Pathogenic (1)Pathogenic (1)0.000000
22. c.497C>T p.S166Fmissense 1VUS favour pathogenic (1)0.000008
23. c.573G>A p.W191Xnonsense 1VUS (1)0.000000
24. c.568G>T p.D190Ymissense 1Likely Pathogenic (1)0.000000
25. c.390G>C p.Q130Hmissense 1VUS (1)0.000000
26. c.581A>C p.N194Tmissense 1VUS (1)0.000008
27. c.592C>G p.L198Vmissense 1VUS favour pathogenic (1)0.000000
28. c.605A>C p.E202Amissense 1VUS (1)0.000000
29. c.575G>T p.R192Lmissense 1Likely Pathogenic (1)0.000000
30. c.532_534delAAG inframe 1Pathogenic (1)0.000000
31. c.490A>G p.K164Emissense 1VUS (1)0.000000
32. c.485G>C p.R162Pmissense 1Likely Pathogenic (1)0.000000
33. c.231C>A p.S77Rmissense 1VUS (1)0.000000
34. c.389A>G p.Q130Rmissense 1Likely Pathogenic (1)0.000000
35. c.512C>A p.A171Dmissense 1VUS (1)0.000000
36. c.626A>C p.E209Amissense 1Likely Pathogenic (1)0.000000
37. c.439G>C p.V147Lmissense 1VUS (1)0.000008
38. c.338del p.Asp113Alafs*2frameshift 1Pathogenic (1)0.000000
39. c.579G>C p.K193Nmissense 1VUS favour pathogenic (1)0.000000
40. c.549G>C p.K183Nmissense 1Likely Pathogenic (1)0.000000
41. c.383T>A p.L128Qmissense 1VUS (1)0.000000
42. c.532A>G p.K178Emissense 1Pathogenic (1)0.000000
43. c.167T>C p.I56Tmissense 1VUS favour pathogenic (1)0.000024
44. c.593T>G p.L198Rmissense 1VUS (1)0.000000
45. c.526G>A p.V176Mmissense 1VUS favour pathogenic (1)0.000000
46. c.590C>G p.A197Gmissense 1VUS (1)0.000000
47. c.488C>G p.A163Gmissense 1VUS (1)0.000000
48. c.368C>T p.T123Mmissense 1VUS (1)0.000025
49. c.292C>T p.R98Xnonsense 1VUS (1)0.000091
50. c.506del p.Leu169Argfs*8frameshift 1VUS (1)0.000000
51. c.607G>C p.G203Rmissense 1Likely Pathogenic (1)0.000000
52. c.285C>A p.D95Emissense 1VUS (1)0.000000
53. c.379G>C p.D127Hmissense 1VUS (1)0.000000
54. c.511G>A p.A171Tmissense 1Likely Pathogenic (1)0.000000

References

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.