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.571-1G>A essential splice site 4VUS (4)0.000017
9. c.281G>A p.R94Hmissense 4Likely Pathogenic (4)0.000000
10. c.388C>T p.R130Cmissense 4Likely Pathogenic (2)Likely Pathogenic (2)0.000000
11. c.281G>T p.R94Lmissense 4Likely Pathogenic (3)Pathogenic (1)0.000000
12. c.860G>A p.W287Xnonsense 4Pathogenic (4)0.000011
13. c.857G>A p.R286Hmissense 3VUS favour pathogenic (3)0.000078
14. c.252A>T p.R84Smissense 2VUS (2)0.000000
15. c.536C>T p.S179Fmissense 2Likely Pathogenic (2)0.000000
16. c.773A>T p.K258Imissense 2VUS favour pathogenic (2)0.000000
17. c.257A>C p.D86Amissense 2Likely Pathogenic (2)0.000008
18. c.251G>C p.R84Tmissense 2VUS favour pathogenic (2)0.000000
19. c.311C>T p.A104Vmissense 2VUS (1)VUS favour pathogenic (1)0.000008
20. c.833G>A p.R278Hmissense 2VUS (1)VUS (1)0.000021
21. c.400C>T p.R134Wmissense 1VUS (1)0.000000
22. c.534G>C p.L178Fmissense 1VUS (1)0.000000
23. c.421C>T p.R141Wmissense 1Pathogenic (1)0.000000
24. c.502G>C p.A168Pmissense 1VUS (1)0.000000
25. c.244G>A p.G82Rmissense 1Likely Pathogenic (1)0.000000
26. c.460-1G>C essential splice site 1VUS (1)0.000000
27. c.249G>C p.E83Dmissense 1VUS (1)0.000000
28. c.330T>G p.F110Lmissense 1Likely Pathogenic (1)0.000000
29. c.767A>G p.Q256Rmissense 1VUS (1)0.000000
30. c.147_149delAGA p.Glu51delinframe 1VUS (1)0.000008
31. c.821+1G>T essential splice site 1Likely Pathogenic (1)0.000000
32. c.238C>T p.P80Smissense 1VUS favour pathogenic (1)0.000000
33. c.256G>T p.D86Ymissense 1VUS (1)0.000000
34. c.652G>T p.V218Lmissense 1VUS favour benign (1)0.000032
35. c.392G>A p.R131Qmissense 1VUS (1)0.000000
36. c.426T>G p.N142Kmissense 1VUS (1)0.000000
37. c.821+1G>C essential splice site 1Pathogenic (1)0.000000
38. c.451C>T p.R151Cmissense 1VUS (1)0.000000
39. c.283A>G p.M95Vmissense 1VUS (1)0.000016
40. c.649A>G p.K217Emissense 1VUS (1)0.000000
41. c.678_680del p.Glu226delinframe 1VUS (1)0.000000
42. c.106G>C p.A36Pmissense 1VUS (1)0.000049
43. c.487G>A p.E163Kmissense 1Likely Pathogenic (1)0.000000
44. c.145G>C p.E49Qmissense 1VUS (1)0.000008
45. c.247G>A p.E83Kmissense 1VUS (1)0.000000
46. c.291G>T p.K97Nmissense 1Likely Pathogenic (1)0.000000
47. c.807C>A p.N269Kmissense 1Likely Pathogenic (1)0.000000
48. c.269T>A p.I90Nmissense 1VUS (1)0.000000
49. c.805A>G p.N269Dmissense 1VUS (1)0.000017

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.