TNNT2 non-truncating variants in HCM cohorts


The table below lists the 55 rare (MAF<0.0001 in ExAC) non-truncating TNNT2 variants identified in a cohort of 2912 HCM patients. When this rare variant frequency of 0.01889 is compared with a background population rate of 0.00214, there is a statistically significant case excess of 0.01675 (p<0.0001), which suggests that approximately 49 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.487_489delGAG inframe 9Pathogenic0.000000
2. c.281G>A p.R94Hmissense 4Likely Pathogenic0.000000
3. c.275G>A p.R92Qmissense 3Pathogenic0.000000
4. c.274C>T p.R92Wmissense 3Pathogenic0.000008
5. c.857G>A p.R286Hmissense 3VUS favour pathogenic0.000078
6. c.856C>T p.R286Cmissense 2VUS favour pathogenic0.000011
7. c.536C>T p.S179Fmissense 2Likely Pathogenic0.000000
8. c.251G>C p.R84Tmissense 2VUS favour pathogenic0.000000
9. c.257A>C p.D86Amissense 2Likely Pathogenic0.000008
10. c.252A>T p.R84Smissense 2VUS0.000000
11. c.236T>A p.I79Nmissense 2Pathogenic0.000000
12. c.388C>T p.R130Cmissense 2Likely Pathogenic0.000000
13. c.773A>T p.K258Imissense 2VUS favour pathogenic0.000000
14. c.311C>T p.A104Vmissense 1VUS favour pathogenic0.000008
15. c.249G>C p.E83Dmissense 1VUS0.000000
16. c.244G>A p.G82Rmissense 1Likely Pathogenic0.000000
17. c.649A>G p.K217Emissense 1VUS0.000000
18. c.330T>G p.F110Lmissense 1Likely Pathogenic0.000000
19. c.785A>G p.N262Smissense 1VUS0.000000
20. c.652G>T p.V218Lmissense 1VUS favour benign0.000032
21. c.421C>T p.R141Wmissense 1Pathogenic0.000000
22. c.238C>T p.P80Smissense 1VUS favour pathogenic0.000000
23. c.283A>G p.M95Vmissense 1VUS0.000016
24. c.106G>C p.A36Pmissense 1VUS0.000049
25. c.833G>A p.R278Hmissense 1VUS0.000021
26. c.281G>T p.R94Lmissense 1Pathogenic0.000000
27. c.247G>A p.E83Kmissense 1VUS0.000000
28. c.833G>C p.R278Pmissense 1VUS favour pathogenic0.000000
29. c.534G>C p.L178Fmissense 1VUS0.000000
30. c.807C>A p.N269Kmissense 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.