TPM1 variants in HCM cohorts


The table below lists the 66 rare (MAF<0.0001 in ExAC) protein-altering TPM1 variants identified in a cohort of 4447 HCM patients (1535 patients from OMGL, 2912 patients from LMM). When this rare variant frequency of 0.01484 is compared with a background population rate of 0.00086, there is a statistically significant case excess of 0.01398 (p<0.0001), which suggests that approximately 62 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 (4447)OMGL classLMM class ExAC frequency
1. c.574G>A p.E192Kmissense 13Likely Pathogenic (13)0.000000
2. c.523G>A p.D175Nmissense 8Pathogenic (4)Pathogenic (4)0.000000
3. c.644C>T p.S215Lmissense 4VUS (1)VUS favour pathogenic (3)0.000008
4. c.82G>C p.D28Hmissense 3VUS (1)VUS favour pathogenic (2)0.000000
5. c.548C>T p.A183Vmissense 3VUS (2)VUS (1)0.000000
6. c.64G>A p.A22Tmissense 2VUS favour pathogenic (2)0.000000
7. c.850A>G p.I284Vmissense 2VUS (1)VUS (1)0.000000
8. c.829G>A p.A277Tmissense 2VUS favour benign (2)0.000034
9. c.841A>G p.M281Vmissense 2VUS (2)0.000026
10. c.797A>G p.K266Rmissense 2VUS (2)0.000042
11. c.746T>G p.L249Wmissense 2Likely Pathogenic (2)0.000000
12. c.676A>C p.K226Qmissense 1VUS favour pathogenic (1)0.000000
13. c.655G>A p.D219Nmissense 1Likely Pathogenic (1)0.000000
14. c.677A>G p.K226Rmissense 1VUS (1)0.000000
15. c.835A>C p.N279Hmissense 1VUS favour pathogenic (1)0.000000
16. c.82G>A p.D28Nmissense 1VUS (1)0.000000
17. c.305C>A p.A102Dmissense 1VUS favour pathogenic (1)0.000000
18. c.58G>A p.D20Nmissense 1VUS (1)0.000000
19. c.475G>A p.D159Nmissense 1VUS (1)0.000000
20. c.761A>G p.D254Gmissense 1VUS (1)0.000000
21. c.302G>C p.R101Pmissense 1VUS (1)0.000000
22. c.762T>G p.D254Emissense 1Likely Pathogenic (1)0.000000
23. c.715G>A p.A239Tmissense 1VUS (1)0.000000
24. c.343G>A p.E115Kmissense 1Likely Pathogenic (1)0.000000
25. c.699G>C p.K233Nmissense 1VUS (1)0.000000
26. c.481A>G p.K161Emissense 1VUS (1)0.000000
27. c.46G>C p.E16Qmissense 1Likely Pathogenic (1)0.000000
28. c.252C>G p.D84Emissense 1VUS (1)0.000008
29. c.790A>G p.K264Emissense 1Likely Pathogenic (1)0.000000
30. c.774C>G p.D258Emissense 1VUS (1)0.000000
31. c.457C>G p.H153Dmissense 1Pathogenic (1)0.000000
32. c.461T>C p.I154Tmissense 1Pathogenic (1)0.000000
33. c.559G>C p.E187Qmissense 1Likely Pathogenic (1)0.000000
34. c.842T>C p.M281Tmissense 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. 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.