TNNI3 variants in HCM cohorts


The table below lists the 63 rare (MAF<0.0001 in ExAC) protein-altering TNNI3 variants identified in a cohort of 2912 HCM patients. When this rare variant frequency of 0.02163 is compared with a background population rate of 0.00228, there is a statistically significant case excess of 0.01935 (p<0.0001), which suggests that approximately 56 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 (2912)LMM class ExAC frequency
1. c.485G>A p.R162Qmissense 8Likely Pathogenic0.000024
2. c.470C>T p.A157Vmissense 8Pathogenic0.000000
3. c.422G>A p.R141Qmissense 5Likely Pathogenic0.000000
4. c.434G>A p.R145Qmissense 4Likely Pathogenic0.000024
5. c.557G>A p.R186Qmissense 3Pathogenic0.000000
6. c.433C>T p.R145Wmissense 3Pathogenic0.000008
7. c.428C>A p.T143Nmissense 3VUS0.000024
8. c.611G>A p.R204Hmissense 3Likely Pathogenic0.000000
9. c.236G>T p.R79Lmissense 2VUS0.000046
10. c.484C>T p.R162Wmissense 2VUS0.000033
11. c.575G>A p.R192Hmissense 2Likely Pathogenic0.000000
12. c.509G>A p.R170Qmissense 2Pathogenic0.000000
13. c.586G>A p.D196Nmissense 2VUS favour pathogenic0.000008
14. c.610C>T p.R204Cmissense 2VUS favour pathogenic0.000000
15. c.431T>C p.L144Pmissense 1Pathogenic0.000000
16. c.575G>T p.R192Lmissense 1Likely Pathogenic0.000000
17. c.592C>G p.L198Vmissense 1VUS favour pathogenic0.000000
18. c.497C>T p.S166Fmissense 1VUS favour pathogenic0.000008
19. c.579G>C p.K193Nmissense 1VUS favour pathogenic0.000000
20. c.433C>G p.R145Gmissense 1Pathogenic0.000000
21. c.532_534delAAG inframe 1Pathogenic0.000000
22. c.526G>A p.V176Mmissense 1VUS favour pathogenic0.000000
23. c.485G>C p.R162Pmissense 1Likely Pathogenic0.000000
24. c.167T>C p.I56Tmissense 1VUS favour pathogenic0.000024
25. c.368C>T p.T123Mmissense 1VUS0.000025
26. c.602T>C p.M201Tmissense 1Likely Pathogenic0.000000
27. c.625G>A p.E209Kmissense 1VUS favour pathogenic0.000000
28. c.568G>T p.D190Ymissense 1Likely Pathogenic0.000000

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.