TNNT2 variants in HCM cohorts


The table below lists the 119 rare (MAF<0.0001 in ExAC) protein-altering TNNT2 variants identified in a cohort of 6103 HCM patients (3191 patients from OMGL, 2912 patients from LMM). When this rare variant frequency of 0.01950 is compared with a background population rate of 0.00242, there is a statistically significant case excess of 0.01708 (p<0.0001), which suggests that approximately 105 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 (6103)OMGL classLMM class ExAC frequency
1. c.487_489delGAG inframe 14Pathogenic (5)Pathogenic (9)0.000000
2. c.236T>A p.I79Nmissense 10Pathogenic (8)Pathogenic (2)0.000000
3. c.274C>T p.R92Wmissense 8Pathogenic (5)Pathogenic (3)0.000008
4. c.856C>T p.R286Cmissense 6Likely Pathogenic (4)VUS favour pathogenic (2)0.000011
5. c.833G>C p.R278Pmissense 6Likely Pathogenic (5)VUS favour pathogenic (1)0.000000
6. c.785A>G p.N262Smissense 5VUS (4)VUS (1)0.000000
7. c.275G>A p.R92Qmissense 4Pathogenic (1)Pathogenic (3)0.000000
8. c.281G>A p.R94Hmissense 4Likely Pathogenic (4)0.000000
9. c.388C>T p.R130Cmissense 4Likely Pathogenic (2)Likely Pathogenic (2)0.000000
10. c.281G>T p.R94Lmissense 4Likely Pathogenic (3)Pathogenic (1)0.000000
11. c.860G>A p.W287Xnonsense 4Pathogenic (4)0.000011
12. c.571-1G>A essential splice site 4VUS (4)0.000017
13. c.857G>A p.R286Hmissense 3VUS favour pathogenic (3)0.000078
14. c.536C>T p.S179Fmissense 2Likely Pathogenic (2)0.000000
15. c.257A>C p.D86Amissense 2Likely Pathogenic (2)0.000008
16. c.251G>C p.R84Tmissense 2VUS favour pathogenic (2)0.000000
17. c.833G>A p.R278Hmissense 2VUS (1)VUS (1)0.000021
18. c.252A>T p.R84Smissense 2VUS (2)0.000000
19. c.311C>T p.A104Vmissense 2VUS (1)VUS favour pathogenic (1)0.000008
20. c.773A>T p.K258Imissense 2VUS favour pathogenic (2)0.000000
21. c.330T>G p.F110Lmissense 1Likely Pathogenic (1)0.000000
22. c.821+1G>T essential splice site 1Likely Pathogenic (1)0.000000
23. c.821+1G>C essential splice site 1Pathogenic (1)0.000000
24. c.678_680del p.Glu226delinframe 1VUS (1)0.000000
25. c.652G>T p.V218Lmissense 1VUS favour benign (1)0.000032
26. c.451C>T p.R151Cmissense 1VUS (1)0.000000
27. c.421C>T p.R141Wmissense 1Pathogenic (1)0.000000
28. c.238C>T p.P80Smissense 1VUS favour pathogenic (1)0.000000
29. c.283A>G p.M95Vmissense 1VUS (1)0.000016
30. c.487G>A p.E163Kmissense 1Likely Pathogenic (1)0.000000
31. c.649A>G p.K217Emissense 1VUS (1)0.000000
32. c.145G>C p.E49Qmissense 1VUS (1)0.000008
33. c.269T>A p.I90Nmissense 1VUS (1)0.000000
34. c.291G>T p.K97Nmissense 1Likely Pathogenic (1)0.000000
35. c.106G>C p.A36Pmissense 1VUS (1)0.000049
36. c.805A>G p.N269Dmissense 1VUS (1)0.000017
37. c.502G>C p.A168Pmissense 1VUS (1)0.000000
38. c.400C>T p.R134Wmissense 1VUS (1)0.000000
39. c.247G>A p.E83Kmissense 1VUS (1)0.000000
40. c.767A>G p.Q256Rmissense 1VUS (1)0.000000
41. c.534G>C p.L178Fmissense 1VUS (1)0.000000
42. c.460-1G>C essential splice site 1VUS (1)0.000000
43. c.256G>T p.D86Ymissense 1VUS (1)0.000000
44. c.147_149delAGA p.Glu51delinframe 1VUS (1)0.000008
45. c.807C>A p.N269Kmissense 1Likely Pathogenic (1)0.000000
46. c.244G>A p.G82Rmissense 1Likely Pathogenic (1)0.000000
47. c.249G>C p.E83Dmissense 1VUS (1)0.000000
48. c.392G>A p.R131Qmissense 1VUS (1)0.000000
49. c.426T>G p.N142Kmissense 1VUS (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.