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.
| No. | Variant (CDS)▼ | Variant (Protein) | Variant Type▼ | Cases (1315)▼ | OMGL class | LMM class | ExAC frequency |
|---|---|---|---|---|---|---|---|
| 1. | c.2711G>A | p.R904H | missense | 2 | Likely Pathogenic (2) | 0.000000 | |
| 2. | c.532G>A | p.G178R | missense | 2 | Likely Pathogenic (2) | 0.000000 | |
| 3. | c.2678C>T | p.A893V | missense | 2 | VUS favour pathogenic (2) | 0.000000 | |
| 4. | c.3856G>A | p.E1286K | missense | 2 | Likely Pathogenic (2) | 0.000016 | |
| 5. | c.1405G>T | p.D469Y | missense | 2 | Likely Pathogenic (2) | 0.000000 | |
| 6. | c.431G>T | p.G144V | missense | 2 | Likely Pathogenic (2) | 0.000000 | |
| 7. | c.5530G>A | p.E1844K | missense | 2 | VUS (2) | 0.000008 | |
| 8. | c.1597A>G | p.I533V | missense | 2 | Likely Pathogenic (2) | 0.000000 | |
| 9. | c.1106G>A | p.R369Q | missense | 2 | Likely Pathogenic (2) | 0.000000 | |
| 10. | c.4300C>T | p.R1434C | missense | 2 | Likely Pathogenic (2) | 0.000000 | |
| 11. | c.1700G>A | p.R567H | missense | 1 | Likely Pathogenic (1) | 0.000016 | |
| 12. | c.4408T>C | p.S1470P | missense | 1 | VUS favour pathogenic (1) | 0.000000 | |
| 13. | c.1892T>C | p.I631T | missense | 1 | VUS (1) | 0.000016 | |
| 14. | c.742A>T | p.I248F | missense | 1 | Likely Pathogenic (1) | 0.000000 | |
| 15. | c.4985G>A | p.R1662H | missense | 1 | VUS favour pathogenic (1) | 0.000057 | |
| 16. | c.3455A>T | p.E1152V | missense | 1 | Likely Pathogenic (1) | 0.000000 | |
| 17. | c.3734T>A | p.L1245Q | missense | 1 | VUS (1) | 0.000000 | |
| 18. | c.4643A>T | p.E1548V | missense | 1 | VUS (1) | 0.000000 | |
| 19. | c.184G>A | p.E62K | missense | 1 | VUS (1) | 0.000008 | |
| 20. | c.2456G>A | p.R819Q | missense | 1 | VUS (1) | 0.000008 | |
| 21. | c.2455C>T | p.R819W | missense | 1 | VUS (1) | 0.000000 | |
| 22. | c.1570A>G | p.I524V | missense | 1 | Likely Pathogenic (1) | 0.000000 | |
| 23. | c.2348G>C | p.R783P | missense | 1 | Likely Pathogenic (1) | 0.000000 | |
| 24. | c.5401G>A | p.E1801K | missense | 1 | Likely Pathogenic (1) | 0.000000 | |
| 25. | c.4348G>A | p.D1450N | missense | 1 | Likely Pathogenic (1) | 0.000008 | |
| 26. | c.602T>C | p.I201T | missense | 1 | Likely Pathogenic (1) | 0.000000 | |
| 27. | c.4048G>A | p.E1350K | missense | 1 | VUS (1) | 0.000000 | |
| 28. | c.3284A>G | p.E1095G | missense | 1 | VUS (1) | 0.000000 | |
| 29. | c.589G>A | p.V197I | missense | 1 | VUS (1) | 0.000016 | |
| 30. | c.4411C>T | p.Q1471X | nonsense | 1 | VUS favour pathogenic (1) | 0.000000 | |
| 31. | c.1791C>A | p.N597K | missense | 1 | Likely Pathogenic (1) | 0.000000 | |
| 32. | c.835G>A | p.A279T | missense | 1 | VUS favour pathogenic (1) | 0.000000 | |
| 33. | c.5380C>G | p.Q1794E | missense | 1 | Likely Pathogenic (1) | 0.000000 | |
| 34. | c.1045A>G | p.M349V | missense | 1 | VUS (1) | 0.000024 | |
| 35. | c.4638G>T | p.E1546D | missense | 1 | VUS (1) | 0.000000 | |
| 36. | c.1888C>T | p.P630S | missense | 1 | VUS (1) | 0.000016 | |
| 37. | c.2441T>G | p.I814S | missense | 1 | VUS (1) | 0.000000 | |
| 38. | c.3982G>A | p.A1328T | missense | 1 | VUS favour pathogenic (1) | 0.000043 | |
| 39. | c.2973G>T | p.K991N | missense | 1 | VUS favour pathogenic (1) | 0.000000 | |
| 40. | c.2710C>T | p.R904C | missense | 1 | Pathogenic (1) | 0.000008 | |
| 41. | c.734G>A | p.G245E | missense | 1 | Likely Pathogenic (1) | 0.000000 | |
| 42. | c.5020G>T | p.V1674L | missense | 1 | VUS (1) | 0.000000 | |
| 43. | c.1630A>G | p.T544A | missense | 1 | VUS (1) | 0.000016 | |
| 44. | c.4004C>T | p.S1335L | missense | 1 | VUS (1) | 0.000033 | |
| 45. | c.4030C>T | p.R1344W | missense | 1 | VUS favour pathogenic (1) | 0.000016 | |
| 46. | c.2683C>G | p.Q895E | missense | 1 | VUS (1) | 0.000000 | |
| 47. | c.2682A>C | p.E894D | missense | 1 | VUS (1) | 0.000000 | |
| 48. | c.541G>A | p.G181R | missense | 1 | Likely Pathogenic (1) | 0.000008 | |
| 49. | c.1573G>A | p.E525K | missense | 1 | Likely Pathogenic (1) | 0.000000 | |
| 50. | c.4720C>T | p.R1574W | missense | 1 | Likely Pathogenic (1) | 0.000000 | |
| 51. | c.2171T>A | p.I724N | missense | 1 | VUS favour pathogenic (1) | 0.000000 | |
| 52. | c.3578G>A | p.R1193H | missense | 1 | Likely Pathogenic (1) | 0.000000 | |
| 53. | c.709C>T | p.R237W | missense | 1 | VUS (1) | 0.000008 | |
| 54. | c.1402T>C | p.F468L | missense | 1 | VUS favour pathogenic (1) | 0.000000 | |
| 55. | c.5740G>A | p.E1914K | missense | 1 | Likely Pathogenic (1) | 0.000000 | |
| 56. | c.728G>A | p.R243H | missense | 1 | Likely Pathogenic (1) | 0.000008 | |
| 57. | c.5329G>A | p.A1777T | missense | 1 | VUS (1) | 0.000041 | |
| 58. | c.3464G>A | p.G1155E | missense | 1 | VUS (1) | 0.000000 | |
| 59. | c.2015G>T | p.C672F | missense | 1 | Likely Pathogenic (1) | 0.000000 |
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.