TTN truncating variants in DCM cohorts


The table below lists the 67 rare (MAF<0.0001 in ExAC) truncating TTN variants identified in a cohort of 460 DCM patients (304 patients from OMGL, 156 patients from LMM). When this rare variant frequency of 0.14565 is compared with a background population rate of 0.00876, there is a statistically significant case excess of 0.13689 (p<0.0001), which suggests that approximately 63 of these variants may be pathogenic.


Source:      Combined (OMGL + LMM)     -     OMGL     -     LMM



No. Variant (CDS) Variant (Protein) Variant Type Cases (460)OMGL classLMM class ExAC frequency
1. c.57995delA p.His19332ProfsX18frameshift 3Likely Pathogenic (3)0.000000
2. c.97417del p.Arg32473Valfs*19frameshift 2VUS (2)0.000000
3. c.46803G>A p.W15601Xnonsense 1VUS (1)0.000000
4. c.98506C>T p.R32836Xnonsense 1VUS (1)0.000000
5. c.46925_46928del p.Lys15642Metfs*10frameshift 1VUS (1)0.000000
6. c.14194C>T p.Q4732Xnonsense 1VUS (1)0.000000
7. c.44272C>T p.R14758Xnonsense 1VUS (1)0.000008
8. c.76822del p.Leu25608*frameshift 1VUS (1)0.000000
9. c.73845delA p.Glu24615AspfsX9frameshift 1Likely Pathogenic (1)0.000000
10. c.67952_67955dup p.Lys22652Asnfs*4frameshift 1VUS (1)0.000000
11. c.85713G>A p.W28571Xnonsense 1VUS (1)0.000000
12. c.41610delA p.Val13871SerfsX7frameshift 1Likely Pathogenic (1)0.000000
13. c.62722C>T p.R20908Xnonsense 1VUS (1)0.000000
14. c.46782C>A p.Tyr15594Xnonsense 1Likely Pathogenic (1)0.000000
15. c.51436C>T p.Q17146Xnonsense 1VUS (1)0.000000
16. c.24019C>T p.R8007Xnonsense 1VUS (1)0.000000
17. c.61495C>T p.R20499Xnonsense 1VUS (1)0.000000
18. c.82470G>A p.W27490Xnonsense 1VUS (1)0.000000
19. c.12587C>A p.S4196Xnonsense 1VUS favour pathogenic (1)0.000016
20. c.99058del p.Glu33020Argfs*41frameshift 1VUS (1)0.000000
21. c.90587delA p.Lys30196ArgfsX94frameshift 1Likely Pathogenic (1)0.000000
22. c.70563dup p.Glu23522Argfs*10frameshift 1VUS (1)0.000000
23. c.98504_98505del p.Arg32835Thrfs*5frameshift 1VUS (1)0.000000
24. c.86229delinsAA p.Ile28744Asnfs*12frameshift 1VUS (1)0.000000
25. c.3034C>T p.Arg1012Xnonsense 1Likely Pathogenic (1)0.000000
26. c.46069_46070delAT p.Met15357ValfsX4frameshift 1Likely Pathogenic (1)0.000000
27. c.60163_60164del p.Ile20055Cysfs*7frameshift 1VUS (1)0.000000
28. c.35083G>T p.E11695Xnonsense 1VUS (1)0.000000
29. c.88727delC p.Thr29576LysfsTer36frameshift 1VUS (1)0.000008
30. c.13900G>T p.E4634Xnonsense 1VUS (1)0.000000
31. c.12358C>T p.Q4120Xnonsense 1VUS (1)0.000008
32. c.57215delG p.Gly19072GlufsX12frameshift 1Likely Pathogenic (1)0.000000
33. c.77421_77422insC p.Ser25808GlnfsX19frameshift 1Likely Pathogenic (1)0.000000
34. c.75633_75636dup p.Val25213Cysfs*25frameshift 1VUS (1)0.000000
35. c.63625C>T p.R21209Xnonsense 1VUS (1)0.000000
36. c.92652_92659del p.Asp30885Serfs*3frameshift 1VUS (1)0.000000
37. c.102949C>T p.Gln34317Xnonsense 1Likely Pathogenic (1)0.000000
38. c.85238del p.Thr28413Ilefs*3frameshift 1VUS (1)0.000000
39. c.44364delC p.Tyr14789ThrfsX15frameshift 1Likely Pathogenic (1)0.000000
40. c.60940del p.Thr20314Leufs*5frameshift 1VUS (1)0.000000
41. c.47314C>T p.R15772Xnonsense 1VUS (1)0.000000
42. c.16077del p.Phe5359Leufs*28frameshift 1VUS (1)0.000000
43. c.56572C>T p.R18858Xnonsense 1VUS (1)0.000027
44. c.69458_69461dupAGAA p.Asn23154LysfsX14frameshift 1Likely Pathogenic (1)0.000000
45. c.76865G>A p.W25622Xnonsense 1VUS (1)0.000000
46. c.93897delT p.Phe31299LeufsX14frameshift 1Likely Pathogenic (1)0.000000
47. c.70200_70203dup p.Ile23402Aspfs*6frameshift 1VUS (1)0.000000
48. c.98265_98268dup p.His32757Asnfs*4frameshift 1VUS (1)0.000000
49. c.11657delA p.Asp3886ValfsX22frameshift 1VUS favour pathogenic (1)0.000000
50. c.63025C>T p.R21009Xnonsense 1VUS (1)0.000000
51. c.85946del p.Val28649Glyfs*20frameshift 1VUS (1)0.000000
52. c.46773T>A p.Tyr15591Xnonsense 1Likely Pathogenic (1)0.000000
53. c.51444del p.Asp17149Ilefs*4frameshift 1VUS (1)0.000000
54. c.31035T>G p.Y10345Xnonsense 1VUS (1)0.000000
55. c.64453C>T p.R21485Xnonsense 1VUS (1)0.000025
56. c.57847+1G>A essential splice site 1Likely Pathogenic (1)0.000000
57. c.12742C>T p.Q4248Xnonsense 1VUS (1)0.000000
58. c.100825C>T p.R33609Xnonsense 1VUS (1)0.000000
59. c.89197_89197+2delGGT essential splice site 1Likely Pathogenic (1)0.000000
60. c.74104C>T p.Q24702Xnonsense 1VUS (1)0.000000
61. c.89787del p.Val29930Cysfs*36frameshift 1VUS (1)0.000000
62. c.86821+2T>A essential splice site 1Likely Pathogenic (1)0.000008
63. c.45307C>T p.Arg15103Xnonsense 1Likely Pathogenic (1)0.000000
64. c.60643_60644del p.Arg20215Glufs*13frameshift 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. Pugh TJ, Kelly MA, Gowrisankar S, Hynes E, Seidman MA, Baxter SM, Bowser M, Harrison B, Aaron D, Mahanta LM, Lakdawala NK, McDermott G, White ET, Rehm HL, Lebo M, Funke BH. The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing. Genet Med. 2014 Aug;16(8):601-8.