TNNT2 non-truncating variants in HCM cohorts

TNNT2 gene summary
Overview of TNNT2 in HCM

The table below lists the 108 rare (MAF<0.0001 in ExAC) non-truncating TNNT2 variants identified in a cohort of 6103 HCM patients (3191 patients from OMGL, 2912 patients from LMM). When this rare variant frequency of 0.01770 is compared with a background population rate of 0.00214, there is a statistically significant case excess of 0.01556 (p<0.0001), which suggests that approximately 95 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.857G>A p.R286Hmissense 3VUS favour pathogenic (3)0.000078
2. c.330T>G p.F110Lmissense 1Likely Pathogenic (1)0.000000
3. c.251G>C p.R84Tmissense 2VUS favour pathogenic (2)0.000000
4. c.281G>T p.R94Lmissense 4Likely Pathogenic (3)Pathogenic (1)0.000000
5. c.785A>G p.N262Smissense 5VUS (4)VUS (1)0.000000
6. c.256G>T p.D86Ymissense 1VUS (1)0.000000
7. c.652G>T p.V218Lmissense 1VUS favour benign (1)0.000032
8. c.426T>G p.N142Kmissense 1VUS (1)0.000000
9. c.311C>T p.A104Vmissense 2VUS (1)VUS favour pathogenic (1)0.000008
10. c.238C>T p.P80Smissense 1VUS favour pathogenic (1)0.000000
11. c.257A>C p.D86Amissense 2Likely Pathogenic (2)0.000008
12. c.252A>T p.R84Smissense 2VUS (2)0.000000
13. c.283A>G p.M95Vmissense 1VUS (1)0.000016
14. c.392G>A p.R131Qmissense 1VUS (1)0.000000
15. c.281G>A p.R94Hmissense 4Likely Pathogenic (4)0.000000
16. c.451C>T p.R151Cmissense 1VUS (1)0.000000
17. c.388C>T p.R130Cmissense 4Likely Pathogenic (2)Likely Pathogenic (2)0.000000
18. c.773A>T p.K258Imissense 2VUS favour pathogenic (2)0.000000
19. c.536C>T p.S179Fmissense 2Likely Pathogenic (2)0.000000
20. c.106G>C p.A36Pmissense 1VUS (1)0.000049
21. c.833G>A p.R278Hmissense 2VUS (1)VUS (1)0.000021
22. c.145G>C p.E49Qmissense 1VUS (1)0.000008
23. c.421C>T p.R141Wmissense 1Pathogenic (1)0.000000
24. c.275G>A p.R92Qmissense 4Pathogenic (1)Pathogenic (3)0.000000
25. c.247G>A p.E83Kmissense 1VUS (1)0.000000
26. c.833G>C p.R278Pmissense 6Likely Pathogenic (5)VUS favour pathogenic (1)0.000000
27. c.807C>A p.N269Kmissense 1Likely Pathogenic (1)0.000000
28. c.805A>G p.N269Dmissense 1VUS (1)0.000017
29. c.269T>A p.I90Nmissense 1VUS (1)0.000000
30. c.534G>C p.L178Fmissense 1VUS (1)0.000000
31. c.291G>T p.K97Nmissense 1Likely Pathogenic (1)0.000000
32. c.502G>C p.A168Pmissense 1VUS (1)0.000000
33. c.856C>T p.R286Cmissense 6Likely Pathogenic (4)VUS favour pathogenic (2)0.000011
34. c.236T>A p.I79Nmissense 10Pathogenic (8)Pathogenic (2)0.000000
35. c.249G>C p.E83Dmissense 1VUS (1)0.000000
36. c.400C>T p.R134Wmissense 1VUS (1)0.000000
37. c.244G>A p.G82Rmissense 1Likely Pathogenic (1)0.000000
38. c.649A>G p.K217Emissense 1VUS (1)0.000000
39. c.274C>T p.R92Wmissense 8Pathogenic (5)Pathogenic (3)0.000008
40. c.487G>A p.E163Kmissense 1Likely Pathogenic (1)0.000000
41. c.767A>G p.Q256Rmissense 1VUS (1)0.000000
42. c.147_149delAGA p.Glu51delinframe 1VUS (1)0.000008
43. c.678_680del p.Glu226delinframe 1VUS (1)0.000000
44. c.487_489delGAG inframe 14Pathogenic (5)Pathogenic (9)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.