MYBPC3 non-truncating variants in HCM cohorts


The table below lists the 338 rare (MAF<0.0001 in ExAC) non-truncating MYBPC3 variants identified in a cohort of 3267 HCM patients. When this rare variant frequency of 0.10346 is compared with a background population rate of 0.01884, there is a statistically significant case excess of 0.08462 (p<0.0001), which suggests that approximately 277 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 (3267)OMGL class ExAC frequency
1. c.1504C>T p.R502Wmissense 59Pathogenic0.000024
2. c.772G>A p.E258Kmissense 47Pathogenic0.000039
3. c.1624G>C p.E542Qmissense 24Pathogenic0.000024
4. c.655G>C p.V219Lmissense 18Likely Pathogenic0.000000
5. c.2429G>A p.R810Hmissense 11VUS0.000033
6. c.3613C>T p.R1205Wmissense 10Likely Pathogenic0.000016
7. c.1483C>G p.R495Gmissense 10Likely Pathogenic0.000000
8. c.3771C>A p.N1257Kmissense 9Likely Pathogenic0.000000
9. c.2459G>A p.R820Qmissense 5VUS0.000016
10. c.3065G>C p.R1022Pmissense 5Likely Pathogenic0.000025
11. c.2308G>A p.D770Nmissense 5Likely Pathogenic0.000008
12. c.1484G>A p.R495Qmissense 4Likely Pathogenic0.000008
13. c.3798C>G p.C1266Wmissense 4VUS0.000000
14. c.442G>A p.G148Rmissense 4Likely Pathogenic0.000042
15. c.3277G>T p.G1093Cmissense 3VUS0.000020
16. c.1123G>A p.V375Mmissense 3VUS0.000009
17. c.710A>C p.Y237Smissense 3Likely Pathogenic0.000000
18. c.2210C>T p.T737Mmissense 3VUS0.000050
19. c.1720C>T p.R574Wmissense 3VUS0.000054
20. c.3763G>A p.A1255Tmissense 3VUS0.000075
21. c.3470C>T p.P1157Lmissense 2VUS0.000093
22. c.2300A>G p.K767Rmissense 2VUS0.000016
23. c.818G>A p.R273Hmissense 2VUS0.000042
24. c.2573G>A p.S858Nmissense 2Likely Pathogenic0.000000
25. c.1505G>A p.R502Qmissense 2Pathogenic0.000000
26. c.1483C>T p.R495Wmissense 2Likely Pathogenic0.000000
27. c.3752A>G p.Y1251Cmissense 2VUS0.000000
28. c.3582_3593delGGGCTACACTGC inframe 2Likely Pathogenic0.000000
29. c.3455_3466del p.Ala1152_Lys1155delinframe 2Likely Pathogenic0.000000
30. c.1828G>A p.D610Nmissense 2VUS0.000000
31. c.2432A>G p.K811Rmissense 2VUS0.000000
32. c.2219G>C p.G740Amissense 2VUS0.000000
33. c.3005G>A p.R1002Qmissense 2VUS0.000046
34. c.1886T>C p.L629Pmissense 2VUS0.000000
35. c.557C>T p.P186Lmissense 2VUS0.000047
36. c.3751T>C p.Y1251Hmissense 2VUS0.000000
37. c.3364A>T p.T1122Smissense 1Likely Pathogenic0.000000
38. c.2708G>A p.G903Dmissense 1Likely Pathogenic0.000000
39. c.2909G>A p.R970Qmissense 1Likely Pathogenic0.000032
40. c.2503C>T p.R835Cmissense 1VUS0.000024
41. c.1455A>T p.K485Nmissense 1VUS0.000000
42. c.2198G>A p.R733Hmissense 1VUS0.000034
43. c.256_258del p.Ser86delinframe 1VUS0.000000
44. c.1685C>T p.A562Vmissense 1VUS0.000008
45. c.701C>A p.T234Nmissense 1Likely Pathogenic0.000000
46. c.1072G>A p.D358Nmissense 1VUS0.000008
47. c.3713T>C p.L1238Pmissense 1Likely Pathogenic0.000000
48. c.373G>T p.A125Smissense 1VUS0.000000
49. c.148A>G p.S50Gmissense 1VUS0.000038
50. c.2953A>G p.K985Emissense 1Pathogenic0.000000
51. c.3614G>C p.R1205Pmissense 1Likely Pathogenic0.000000
52. c.3373G>A p.V1125Mmissense 1VUS0.000022
53. c.2249C>T p.T750Mmissense 1Likely Pathogenic0.000024
54. c.1756C>G p.P586Amissense 1Likely Pathogenic0.000000
55. c.1828G>C p.D610Hmissense 1VUS0.000058
56. c.1789C>T p.R597Wmissense 1VUS0.000038
57. c.1456T>G p.W486Gmissense 1VUS0.000000
58. c.1097A>C p.Q366Pmissense 1VUS0.000000
59. c.1021G>A p.G341Smissense 1VUS0.000025
60. c.3656T>C p.L1219Pmissense 1VUS0.000000
61. c.532G>A p.V178Mmissense 1VUS0.000020
62. c.1213A>G p.M405Vmissense 1VUS0.000000
63. c.3739G>A p.D1247Nmissense 1VUS0.000000
64. c.3206C>A p.P1069Hmissense 1Likely Pathogenic0.000000
65. c.2381C>A p.P794Qmissense 1VUS0.000000
66. c.3019T>C p.W1007Rmissense 1VUS0.000000
67. c.3452C>T p.A1151Vmissense 1VUS0.000078
68. c.2873C>T p.T958Imissense 1VUS0.000065
69. c.2269G>A p.V757Mmissense 1VUS0.000066
70. c.241G>T p.V81Fmissense 1VUS0.000000
71. c.1231A>G p.I411Vmissense 1VUS0.000000
72. c.1471G>A p.V491Mmissense 1VUS0.000058
73. c.2197C>T p.R733Cmissense 1Likely Pathogenic0.000085
74. c.1291G>A p.D431Nmissense 1VUS0.000028
75. c.799C>G p.L267Vmissense 1VUS0.000080
76. c.1037G>A p.R346Hmissense 1VUS0.000000
77. c.188G>A p.R63Qmissense 1VUS0.000039
78. c.3334_3351del p.Trp1112_Glu1117delinframe 1Likely Pathogenic0.000000
79. c.844C>T p.R282Wmissense 1Likely Pathogenic0.000000
80. c.2834G>A p.R945Qmissense 1VUS0.000000
81. c.3572C>T p.S1191Lmissense 1VUS0.000016
82. c.3316G>A p.D1106Nmissense 1VUS0.000061
83. c.2504G>T p.R835Lmissense 1Likely Pathogenic0.000074
84. c.365C>A p.A122Dmissense 1VUS0.000000
85. c.1731G>C p.W577Cmissense 1VUS0.000000
86. c.1080G>C p.K360Nmissense 1VUS0.000000
87. c.1112C>T p.P371Lmissense 1VUS0.000028
88. c.1433C>T p.S478Lmissense 1Likely Pathogenic0.000017
89. c.49C>T p.R17Wmissense 1VUS0.000023
90. c.994G>A p.E332Kmissense 1VUS0.000009
91. c.3614G>A p.R1205Qmissense 1VUS0.000016
92. c.1153G>A p.V385Mmissense 1VUS0.000010
93. c.2968C>G p.P990Amissense 1Likely Pathogenic0.000000
94. c.3728C>G p.P1243Rmissense 1VUS0.000000
95. c.146_148delTCA p.Ile49delinframe 1VUS0.000039
96. c.3064C>T p.R1022Cmissense 1VUS0.000008
97. c.2449C>T p.R817Wmissense 1VUS0.000000
98. c.1841A>G p.Y614Cmissense 1VUS0.000000
99. c.2265C>A p.N755Kmissense 1Pathogenic0.000000
100. c.2030C>T p.P677Lmissense 1VUS0.000000
101. c.1A>T p.Met1?missense 1Likely Pathogenic0.000000
102. c.1591G>A p.G531Rmissense 1Likely Pathogenic0.000017
103. c.1174G>T p.A392Smissense 1VUS0.000000
104. c.1790G>A p.R597Qmissense 1VUS0.000000
105. c.3676C>T p.R1226Cmissense 1VUS0.000058
106. c.1021G>C p.G341Rmissense 1VUS0.000000
107. c.187C>T p.R63Wmissense 1VUS0.000077
108. c.3256T>C p.W1086Rmissense 1VUS0.000000
109. c.631G>A p.D211Nmissense 1VUS0.000009

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.