TNNI3 non-truncating variants in HCM cohorts


The table below lists the 66 rare (MAF<0.0001 in ExAC) non-truncating TNNI3 variants identified in a cohort of 3135 HCM patients. When this rare variant frequency of 0.02105 is compared with a background population rate of 0.00186, there is a statistically significant case excess of 0.01919 (p<0.0001), which suggests that approximately 60 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 (3135)OMGL class ExAC frequency
1. c.433C>T p.R145Wmissense 10Pathogenic0.000008
2. c.484C>T p.R162Wmissense 7VUS0.000033
3. c.422G>A p.R141Qmissense 6Likely Pathogenic0.000000
4. c.586G>A p.D196Nmissense 4Likely Pathogenic0.000008
5. c.485G>A p.R162Qmissense 4VUS0.000024
6. c.470C>T p.A157Vmissense 3Likely Pathogenic0.000000
7. c.407G>A p.R136Qmissense 3Likely Pathogenic0.000008
8. c.596G>A p.S199Nmissense 2Likely Pathogenic0.000000
9. c.557G>A p.R186Qmissense 2Pathogenic0.000000
10. c.433C>G p.R145Gmissense 2Pathogenic0.000000
11. c.611G>A p.R204Hmissense 1Likely Pathogenic0.000000
12. c.511G>A p.A171Tmissense 1Likely Pathogenic0.000000
13. c.431T>C p.L144Pmissense 1Likely Pathogenic0.000000
14. c.379G>C p.D127Hmissense 1VUS0.000000
15. c.593T>G p.L198Rmissense 1VUS0.000000
16. c.626A>C p.E209Amissense 1Likely Pathogenic0.000000
17. c.390G>C p.Q130Hmissense 1VUS0.000000
18. c.389A>G p.Q130Rmissense 1Likely Pathogenic0.000000
19. c.490A>G p.K164Emissense 1VUS0.000000
20. c.607G>C p.G203Rmissense 1Likely Pathogenic0.000000
21. c.581A>C p.N194Tmissense 1VUS0.000008
22. c.285C>A p.D95Emissense 1VUS0.000000
23. c.549G>C p.K183Nmissense 1Likely Pathogenic0.000000
24. c.625G>A p.E209Kmissense 1VUS0.000000
25. c.590C>G p.A197Gmissense 1VUS0.000000
26. c.532A>G p.K178Emissense 1Pathogenic0.000000
27. c.439G>C p.V147Lmissense 1VUS0.000008
28. c.383T>A p.L128Qmissense 1VUS0.000000
29. c.605A>C p.E202Amissense 1VUS0.000000
30. c.602T>C p.M201Tmissense 1Likely Pathogenic0.000000
31. c.488C>G p.A163Gmissense 1VUS0.000000
32. c.231C>A p.S77Rmissense 1VUS0.000000
33. c.512C>A p.A171Dmissense 1VUS0.000000

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.