MYBPC3 non-truncating variants in HCM cohorts

The table below lists the 272 rare (MAF<0.0001 in ExAC) non-truncating MYBPC3 variants identified in a cohort of 2912 HCM patients. When this rare variant frequency of 0.09341 is compared with a background population rate of 0.01884, there is a statistically significant case excess of 0.07457 (p<0.0001), which suggests that approximately 218 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.1504C>T p.R502Wmissense 45Pathogenic0.000024
2. c.772G>A p.E258Kmissense 21Pathogenic0.000039
3. c.1624G>C p.E542Qmissense 17Likely Pathogenic0.000024
4. c.1484G>A p.R495Qmissense 10VUS favour pathogenic0.000008
5. c.2429G>A p.R810Hmissense 8VUS favour pathogenic0.000033
6. c.655G>C p.V219Lmissense 8Likely Pathogenic0.000000
7. c.442G>A p.G148Rmissense 7VUS favour pathogenic0.000042
8. c.2308G>A p.D770Nmissense 6Likely Pathogenic0.000008
9. c.1505G>A p.R502Qmissense 6Pathogenic0.000000
10. c.2374T>C p.W792Rmissense 5Likely Pathogenic0.000000
11. c.3064C>T p.R1022Cmissense 4VUS favour pathogenic0.000008
12. c.1483C>G p.R495Gmissense 4Likely Pathogenic0.000000
13. c.2573G>A p.S858Nmissense 4VUS favour pathogenic0.000000
14. c.3742_3759dup p.Gly1248_Cys1253dupinframe 4Likely Pathogenic0.000000
15. c.710A>C p.Y237Smissense 3Likely Pathogenic0.000000
16. c.355G>A p.E119Kmissense 3VUS0.000000
17. c.2450G>A p.R817Qmissense 3VUS favour pathogenic0.000016
18. c.2873C>T p.T958Imissense 3VUS favour benign0.000065
19. c.3767_3769delCCA p.Thr1256delinframe 3Likely Pathogenic0.000000
20. c.1591G>A p.G531Rmissense 3VUS favour pathogenic0.000017
21. c.1828G>A p.D610Nmissense 3VUS0.000000
22. c.1790G>A p.R597Qmissense 2VUS favour pathogenic0.000000
23. c.1766G>A p.R589Hmissense 2VUS0.000000
24. c.1934C>T p.P645Lmissense 2VUS0.000000
25. c.2882C>T p.P961Lmissense 2VUS0.000048
26. c.1483C>T p.R495Wmissense 2VUS favour pathogenic0.000000
27. c.1513_1515delAAG inframe 2VUS favour pathogenic0.000000
28. c.814C>T p.R272Cmissense 2VUS0.000083
29. c.2320G>A p.A774Tmissense 2VUS0.000000
30. c.532G>A p.V178Mmissense 2VUS favour pathogenic0.000020
31. c.1828G>C p.D610Hmissense 2VUS favour benign0.000058
32. c.636C>G p.S212Rmissense 2VUS favour pathogenic0.000000
33. c.1037G>A p.R346Hmissense 2VUS0.000000
34. c.844C>T p.R282Wmissense 1VUS favour pathogenic0.000000
35. c.223G>A p.D75Nmissense 1VUS favour pathogenic0.000091
36. c.2993A>G p.Q998Rmissense 1VUS favour pathogenic0.000000
37. c.1021G>A p.G341Smissense 1VUS favour pathogenic0.000025
38. c.481C>A p.P161Tmissense 1VUS favour pathogenic0.000041
39. c.2518G>A p.V840Mmissense 1VUS0.000016
40. c.1672G>A p.A558Tmissense 1VUS0.000008
41. c.2312T>C p.V771Amissense 1VUS0.000000
42. c.373G>T p.A125Smissense 1VUS0.000000
43. c.3083C>G p.T1028Smissense 1VUS0.000000
44. c.3415G>A p.V1139Imissense 1VUS0.000087
45. c.2210C>T p.T737Mmissense 1VUS0.000050
46. c.2528_2536delAGATGCGCG p.Glu843_Arg845delinframe 1Pathogenic0.000000
47. c.2723A>G p.Y908Cmissense 1VUS0.000062
48. c.1586C>G p.T529Smissense 1VUS favour pathogenic0.000000
49. c.2436G>T p.K812Nmissense 1VUS0.000000
50. c.2459G>A p.R820Qmissense 1Likely Pathogenic0.000016
51. c.1591G>C p.G531Rmissense 1VUS favour pathogenic0.000017
52. c.3797G>A p.C1266Ymissense 1Likely Pathogenic0.000000
53. c.1397T>A p.M466Kmissense 1VUS0.000008
54. c.2197C>T p.R733Cmissense 1VUS0.000085
55. c.2269G>A p.V757Mmissense 1VUS0.000066
56. c.1960C>T p.R654Cmissense 1VUS favour benign0.000008
57. c.932C>T p.S311Lmissense 1VUS0.000000
58. c.2828G>A p.R943Qmissense 1VUS0.000025
59. c.1505G>T p.R502Lmissense 1VUS favour pathogenic0.000000
60. c.104G>A p.R35Qmissense 1VUS0.000079
61. c.3548T>G p.F1183Cmissense 1Likely Pathogenic0.000000
62. c.451G>A p.D151Nmissense 1VUS0.000041
63. c.436A>C p.T146Pmissense 1VUS0.000000
64. c.290C>T p.A97Vmissense 1VUS favour pathogenic0.000000
65. c.326C>T p.A109Vmissense 1VUS0.000000
66. c.1188G>T p.W396Cmissense 1VUS0.000000
67. c.931T>A p.S311Tmissense 1VUS0.000000
68. c.1343T>C p.F448Smissense 1Likely Pathogenic0.000000
69. c.1778C>T p.S593Fmissense 1VUS favour pathogenic0.000034
70. c.713G>A p.R238Hmissense 1VUS0.000074
71. c.2560A>G p.M854Vmissense 1VUS0.000000
72. c.3746G>T p.G1249Vmissense 1VUS0.000000
73. c.3605G>A p.C1202Ymissense 1Likely Pathogenic0.000000
74. c.3098G>A p.R1033Qmissense 1VUS0.000000
75. c.2449C>T p.R817Wmissense 1VUS0.000000
76. c.2939G>A p.R980Hmissense 1VUS0.000000
77. c.1841A>G p.Y614Cmissense 1VUS favour pathogenic0.000000
78. c.518C>A p.T173Nmissense 1VUS0.000000
79. c.1950C>G p.D650Emissense 1VUS0.000000
80. c.3373G>A p.V1125Mmissense 1VUS favour pathogenic0.000022
81. c.1456T>G p.W486Gmissense 1Likely Pathogenic0.000000
82. c.1213A>G p.M405Vmissense 1Pathogenic0.000000
83. c.3580G>A p.A1194Tmissense 1VUS0.000008
84. c.3763G>A p.A1255Tmissense 1VUS favour pathogenic0.000075
85. c.2234A>G p.D745Gmissense 1VUS0.000000
86. c.1540A>G p.I514Vmissense 1VUS0.000008
87. c.3049G>A p.E1017Kmissense 1VUS favour benign0.000085
88. c.2938C>T p.R980Cmissense 1VUS0.000062
89. c.2170C>T p.R724Wmissense 1VUS0.000019
90. c.3676C>T p.R1226Cmissense 1VUS0.000058
91. c.1358C>T p.P453Lmissense 1VUS0.000008
92. c.1535T>A p.L512Qmissense 1VUS favour pathogenic0.000000
93. c.1294G>A p.A432Tmissense 1VUS0.000037
94. c.2557G>A p.G853Smissense 1VUS0.000008
95. c.1418T>C p.F473Smissense 1VUS0.000000
96. c.853G>A p.D285Nmissense 1VUS0.000000
97. c.3065G>A p.R1022Hmissense 1VUS favour pathogenic0.000000
98. c.3281A>T p.N1094Imissense 1VUS0.000000
99. c.3065G>C p.R1022Pmissense 1VUS favour pathogenic0.000025
100. c.2671C>T p.R891Wmissense 1Likely Pathogenic0.000031
101. c.2641G>A p.V881Imissense 1VUS0.000018
102. c.3742G>A p.G1248Rmissense 1VUS0.000033
103. c.103C>T p.R35Wmissense 1VUS0.000056
104. c.2654C>T p.T885Mmissense 1VUS0.000022
105. c.3791G>A p.C1264Ymissense 1VUS0.000008
106. c.3G>C p.Met1?missense 1Likely Pathogenic0.000000
107. c.3277G>T p.G1093Cmissense 1VUS0.000020
108. c.2525A>G p.Y842Cmissense 1VUS0.000000
109. c.3413G>C p.R1138Pmissense 1VUS0.000000
110. c.2533C>T p.R845Cmissense 1VUS favour pathogenic0.000000
111. c.566T>A p.V189Dmissense 1VUS0.000000


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. 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.