MYH7 variants in DCM cohorts


The table below lists the 70 rare (MAF<0.0001 in ExAC) protein-altering MYH7 variants identified in a cohort of 1315 DCM patients (559 patients from OMGL, 756 patients from LMM). When this rare variant frequency of 0.05323 is compared with a background population rate of 0.01398, there is a statistically significant case excess of 0.03925 (p<0.0001), which suggests that approximately 52 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 (1315)OMGL classLMM class ExAC frequency
1. c.3856G>A p.E1286Kmissense 2Likely Pathogenic (2)0.000016
2. c.1106G>A p.R369Qmissense 2Likely Pathogenic (2)0.000000
3. c.532G>A p.G178Rmissense 2Likely Pathogenic (2)0.000000
4. c.5530G>A p.E1844Kmissense 2VUS (2)0.000008
5. c.431G>T p.G144Vmissense 2Likely Pathogenic (2)0.000000
6. c.2711G>A p.R904Hmissense 2Likely Pathogenic (2)0.000000
7. c.4300C>T p.R1434Cmissense 2Likely Pathogenic (2)0.000000
8. c.2678C>T p.A893Vmissense 2VUS favour pathogenic (2)0.000000
9. c.1405G>T p.D469Ymissense 2Likely Pathogenic (2)0.000000
10. c.1597A>G p.I533Vmissense 2Likely Pathogenic (2)0.000000
11. c.3982G>A p.A1328Tmissense 1VUS favour pathogenic (1)0.000043
12. c.3464G>A p.G1155Emissense 1VUS (1)0.000000
13. c.3734T>A p.L1245Qmissense 1VUS (1)0.000000
14. c.2456G>A p.R819Qmissense 1VUS (1)0.000008
15. c.602T>C p.I201Tmissense 1Likely Pathogenic (1)0.000000
16. c.835G>A p.A279Tmissense 1VUS favour pathogenic (1)0.000000
17. c.2973G>T p.K991Nmissense 1VUS favour pathogenic (1)0.000000
18. c.4643A>T p.E1548Vmissense 1VUS (1)0.000000
19. c.734G>A p.G245Emissense 1Likely Pathogenic (1)0.000000
20. c.2015G>T p.C672Fmissense 1Likely Pathogenic (1)0.000000
21. c.4048G>A p.E1350Kmissense 1VUS (1)0.000000
22. c.5380C>G p.Q1794Emissense 1Likely Pathogenic (1)0.000000
23. c.2171T>A p.I724Nmissense 1VUS favour pathogenic (1)0.000000
24. c.2710C>T p.R904Cmissense 1Pathogenic (1)0.000008
25. c.4720C>T p.R1574Wmissense 1Likely Pathogenic (1)0.000000
26. c.2455C>T p.R819Wmissense 1VUS (1)0.000000
27. c.1888C>T p.P630Smissense 1VUS (1)0.000016
28. c.1573G>A p.E525Kmissense 1Likely Pathogenic (1)0.000000
29. c.1700G>A p.R567Hmissense 1Likely Pathogenic (1)0.000016
30. c.589G>A p.V197Imissense 1VUS (1)0.000016
31. c.4030C>T p.R1344Wmissense 1VUS favour pathogenic (1)0.000016
32. c.4408T>C p.S1470Pmissense 1VUS favour pathogenic (1)0.000000
33. c.3284A>G p.E1095Gmissense 1VUS (1)0.000000
34. c.1570A>G p.I524Vmissense 1Likely Pathogenic (1)0.000000
35. c.1045A>G p.M349Vmissense 1VUS (1)0.000024
36. c.1630A>G p.T544Amissense 1VUS (1)0.000016
37. c.1402T>C p.F468Lmissense 1VUS favour pathogenic (1)0.000000
38. c.4638G>T p.E1546Dmissense 1VUS (1)0.000000
39. c.2683C>G p.Q895Emissense 1VUS (1)0.000000
40. c.3578G>A p.R1193Hmissense 1Likely Pathogenic (1)0.000000
41. c.3455A>T p.E1152Vmissense 1Likely Pathogenic (1)0.000000
42. c.5740G>A p.E1914Kmissense 1Likely Pathogenic (1)0.000000
43. c.742A>T p.I248Fmissense 1Likely Pathogenic (1)0.000000
44. c.4004C>T p.S1335Lmissense 1VUS (1)0.000033
45. c.2348G>C p.R783Pmissense 1Likely Pathogenic (1)0.000000
46. c.5020G>T p.V1674Lmissense 1VUS (1)0.000000
47. c.709C>T p.R237Wmissense 1VUS (1)0.000008
48. c.5401G>A p.E1801Kmissense 1Likely Pathogenic (1)0.000000
49. c.2441T>G p.I814Smissense 1VUS (1)0.000000
50. c.4985G>A p.R1662Hmissense 1VUS favour pathogenic (1)0.000057
51. c.541G>A p.G181Rmissense 1Likely Pathogenic (1)0.000008
52. c.1892T>C p.I631Tmissense 1VUS (1)0.000016
53. c.1791C>A p.N597Kmissense 1Likely Pathogenic (1)0.000000
54. c.4348G>A p.D1450Nmissense 1Likely Pathogenic (1)0.000008
55. c.4411C>T p.Q1471Xnonsense 1VUS favour pathogenic (1)0.000000
56. c.2682A>C p.E894Dmissense 1VUS (1)0.000000
57. c.5329G>A p.A1777Tmissense 1VUS (1)0.000041
58. c.728G>A p.R243Hmissense 1Likely Pathogenic (1)0.000008
59. c.184G>A p.E62Kmissense 1VUS (1)0.000008

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.