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.106G>C p.A36Pmissense 1VUS (1)0.000049
2. c.145G>C p.E49Qmissense 1VUS (1)0.000008
3. c.147_149delAGA p.Glu51delinframe 1VUS (1)0.000008
4. c.236T>A p.I79Nmissense 10Pathogenic (8)Pathogenic (2)0.000000
5. c.238C>T p.P80Smissense 1VUS favour pathogenic (1)0.000000
6. c.244G>A p.G82Rmissense 1Likely Pathogenic (1)0.000000
7. c.247G>A p.E83Kmissense 1VUS (1)0.000000
8. c.249G>C p.E83Dmissense 1VUS (1)0.000000
9. c.251G>C p.R84Tmissense 2VUS favour pathogenic (2)0.000000
10. c.252A>T p.R84Smissense 2VUS (2)0.000000
11. c.256G>T p.D86Ymissense 1VUS (1)0.000000
12. c.257A>C p.D86Amissense 2Likely Pathogenic (2)0.000008
13. c.269T>A p.I90Nmissense 1VUS (1)0.000000
14. c.274C>T p.R92Wmissense 8Pathogenic (5)Pathogenic (3)0.000008
15. c.275G>A p.R92Qmissense 4Pathogenic (1)Pathogenic (3)0.000000
16. c.281G>T p.R94Lmissense 4Likely Pathogenic (3)Pathogenic (1)0.000000
17. c.281G>A p.R94Hmissense 4Likely Pathogenic (4)0.000000
18. c.283A>G p.M95Vmissense 1VUS (1)0.000016
19. c.291G>T p.K97Nmissense 1Likely Pathogenic (1)0.000000
20. c.311C>T p.A104Vmissense 2VUS (1)VUS favour pathogenic (1)0.000008
21. c.330T>G p.F110Lmissense 1Likely Pathogenic (1)0.000000
22. c.388C>T p.R130Cmissense 4Likely Pathogenic (2)Likely Pathogenic (2)0.000000
23. c.392G>A p.R131Qmissense 1VUS (1)0.000000
24. c.400C>T p.R134Wmissense 1VUS (1)0.000000
25. c.421C>T p.R141Wmissense 1Pathogenic (1)0.000000
26. c.426T>G p.N142Kmissense 1VUS (1)0.000000
27. c.451C>T p.R151Cmissense 1VUS (1)0.000000
28. c.460-1G>C essential splice site 1VUS (1)0.000000
29. c.487_489delGAG inframe 14Pathogenic (5)Pathogenic (9)0.000000
30. c.487G>A p.E163Kmissense 1Likely Pathogenic (1)0.000000
31. c.502G>C p.A168Pmissense 1VUS (1)0.000000
32. c.534G>C p.L178Fmissense 1VUS (1)0.000000
33. c.536C>T p.S179Fmissense 2Likely Pathogenic (2)0.000000
34. c.571-1G>A essential splice site 4VUS (4)0.000017
35. c.649A>G p.K217Emissense 1VUS (1)0.000000
36. c.652G>T p.V218Lmissense 1VUS favour benign (1)0.000032
37. c.678_680del p.Glu226delinframe 1VUS (1)0.000000
38. c.767A>G p.Q256Rmissense 1VUS (1)0.000000
39. c.773A>T p.K258Imissense 2VUS favour pathogenic (2)0.000000
40. c.785A>G p.N262Smissense 5VUS (4)VUS (1)0.000000
41. c.805A>G p.N269Dmissense 1VUS (1)0.000017
42. c.807C>A p.N269Kmissense 1Likely Pathogenic (1)0.000000
43. c.821+1G>T essential splice site 1Likely Pathogenic (1)0.000000
44. c.821+1G>C essential splice site 1Pathogenic (1)0.000000
45. c.833G>C p.R278Pmissense 6Likely Pathogenic (5)VUS favour pathogenic (1)0.000000
46. c.833G>A p.R278Hmissense 2VUS (1)VUS (1)0.000021
47. c.856C>T p.R286Cmissense 6Likely Pathogenic (4)VUS favour pathogenic (2)0.000011
48. c.857G>A p.R286Hmissense 3VUS favour pathogenic (3)0.000078
49. c.860G>A p.W287Xnonsense 4Pathogenic (4)0.000011

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.