MYBPC3 variants in HCM cohorts

The table below lists the 540 rare (MAF<0.0001 in ExAC) protein-altering MYBPC3 variants identified in a cohort of 2912 HCM patients. When this rare variant frequency of 0.18544 is compared with a background population rate of 0.01970, there is a statistically significant case excess of 0.16574 (p<0.0001), which suggests that approximately 481 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.2373_2374insG p.Trp792ValfsTer41frameshift 26Pathogenic0.000037
3. c.772G>A p.E258Kmissense 21Pathogenic0.000039
4. c.1928-2A>G essential splice site 20Pathogenic0.000000
5. c.1624G>C p.E542Qmissense 17Likely Pathogenic0.000024
6. c.3330+2T>G essential splice site 11Pathogenic0.000000
7. c.1484G>A p.R495Qmissense 10VUS favour pathogenic0.000008
8. c.2309-2A>G essential splice site 9Pathogenic0.000000
9. c.3697C>T p.Q1233Xnonsense 9Pathogenic0.000008
10. c.2429G>A p.R810Hmissense 8VUS favour pathogenic0.000033
11. c.655G>C p.V219Lmissense 8Likely Pathogenic0.000000
12. c.2670G>A p.W890Xnonsense 7Pathogenic0.000000
13. c.442G>A p.G148Rmissense 7VUS favour pathogenic0.000042
14. c.2827C>T p.R943Xnonsense 7Pathogenic0.000017
15. c.1505G>A p.R502Qmissense 6Pathogenic0.000000
16. c.3226_3227insT frameshift 6Pathogenic0.000000
17. c.2864_2865delCT frameshift 6Pathogenic0.000000
18. c.2308G>A p.D770Nmissense 6Likely Pathogenic0.000008
19. c.2374T>C p.W792Rmissense 5Likely Pathogenic0.000000
20. c.913_914delTT frameshift 5Pathogenic0.000000
21. c.821+1G>A essential splice site 4Pathogenic0.000043
22. c.2905+1G>A essential splice site 4Pathogenic0.000000
23. c.3742_3759dup p.Gly1248_Cys1253dupinframe 4Likely Pathogenic0.000000
24. c.2454G>A p.W818Xnonsense 4Pathogenic0.000000
25. c.3064C>T p.R1022Cmissense 4VUS favour pathogenic0.000008
26. c.2096delC frameshift 4Pathogenic0.000000
27. c.1483C>G p.R495Gmissense 4Likely Pathogenic0.000000
28. c.2573G>A p.S858Nmissense 4VUS favour pathogenic0.000000
29. c.2182G>T p.E728Xnonsense 4Pathogenic0.000000
30. c.26-2A>G essential splice site 4Pathogenic0.000051
31. c.3491-2A>T essential splice site 3Pathogenic0.000000
32. c.2873C>T p.T958Imissense 3VUS favour benign0.000065
33. c.2311_2312insG p.Val771GlyfsX62frameshift 3Pathogenic0.000000
34. c.1591G>A p.G531Rmissense 3VUS favour pathogenic0.000017
35. c.3767_3769delCCA p.Thr1256delinframe 3Likely Pathogenic0.000000
36. c.1828G>A p.D610Nmissense 3VUS0.000000
37. c.710A>C p.Y237Smissense 3Likely Pathogenic0.000000
38. c.2450G>A p.R817Qmissense 3VUS favour pathogenic0.000016
39. c.3233G>A p.W1078Xnonsense 3Pathogenic0.000022
40. c.3190+1G>A essential splice site 3Pathogenic0.000000
41. c.2920C>T p.Q974Xnonsense 3Pathogenic0.000000
42. c.355G>A p.E119Kmissense 3VUS0.000000
43. c.2905C>T p.Q969Xnonsense 3Pathogenic0.000000
44. c.636C>G p.S212Rmissense 2VUS favour pathogenic0.000000
45. c.1897+1G>A essential splice site 2Pathogenic0.000000
46. c.1828G>C p.D610Hmissense 2VUS favour benign0.000058
47. c.1357_1358delCC frameshift 2Pathogenic0.000000
48. c.1863delC p.Phe621LeufsX42frameshift 2Pathogenic0.000000
49. c.3192_3193insC p.Lys1065GlnfsX12frameshift 2Pathogenic0.000000
50. c.1790G>A p.R597Qmissense 2VUS favour pathogenic0.000000
51. c.1483C>T p.R495Wmissense 2VUS favour pathogenic0.000000
52. c.3624_3625insC p.Lys1209GlnfsX33frameshift 2Pathogenic0.000000
53. c.2943_2947delGACCA frameshift 2Pathogenic0.000000
54. c.999C>G p.Y333Xnonsense 2Pathogenic0.000000
55. c.1766G>A p.R589Hmissense 2VUS0.000000
56. c.927-2A>G essential splice site 2Pathogenic0.000000
57. c.2558delG frameshift 2Pathogenic0.000000
58. c.1895delT p.Met632ArgfsX31frameshift 2Pathogenic0.000000
59. c.2882C>T p.P961Lmissense 2VUS0.000048
60. c.1037G>A p.R346Hmissense 2VUS0.000000
61. c.772+1G>A essential splice site 2Pathogenic0.000000
62. c.3627+1G>A essential splice site 2Pathogenic0.000000
63. c.2604_2605delinsA p.S871fsframeshift 2Pathogenic0.000000
64. c.532G>A p.V178Mmissense 2VUS favour pathogenic0.000020
65. c.1210C>T p.Q404Xnonsense 2Pathogenic0.000000
66. c.3190+2T>G essential splice site 2Pathogenic0.000016
67. c.436_437insA p.Thr146AsnfsX7frameshift 2Pathogenic0.000000
68. c.1869C>A p.C623Xnonsense 2Pathogenic0.000000
69. c.3624delC frameshift 2Pathogenic0.000000
70. c.1934C>T p.P645Lmissense 2VUS0.000000
71. c.814C>T p.R272Cmissense 2VUS0.000083
72. c.2320G>A p.A774Tmissense 2VUS0.000000
73. c.1513_1515delAAG inframe 2VUS favour pathogenic0.000000
74. c.1456T>G p.W486Gmissense 1Likely Pathogenic0.000000
75. c.2875_2876delAC p.Thr959GlyfsX91frameshift 1Pathogenic0.000000
76. c.3690_3691delCA p.Phe1230LeufsX11frameshift 1Pathogenic0.000000
77. c.2437A>T p.K813Xnonsense 1Pathogenic0.000000
78. c.1090+1G>T essential splice site 1Pathogenic0.000000
79. c.3253G>T p.E1085Xnonsense 1Pathogenic0.000000
80. c.3476_3477delTT frameshift 1Pathogenic0.000000
81. c.290C>T p.A97Vmissense 1VUS favour pathogenic0.000000
82. c.3797G>A p.C1266Ymissense 1Likely Pathogenic0.000000
83. c.2780_2781delCA frameshift 1Pathogenic0.000000
84. c.993_994insT p.E332Xnonsense 1Pathogenic0.000000
85. c.2528_2536delAGATGCGCG p.Glu843_Arg845delinframe 1Pathogenic0.000000
86. c.1351+1G>A essential splice site 1Pathogenic0.000000
87. c.436A>C p.T146Pmissense 1VUS0.000000
88. c.481C>A p.P161Tmissense 1VUS favour pathogenic0.000041
89. c.506-1G>T essential splice site 1Pathogenic0.000000
90. c.2234A>G p.D745Gmissense 1VUS0.000000
91. c.326C>T p.A109Vmissense 1VUS0.000000
92. c.1021G>A p.G341Smissense 1VUS favour pathogenic0.000025
93. c.2040_2041insT p.Val681CysfsX12frameshift 1Pathogenic0.000000
94. c.3580G>A p.A1194Tmissense 1VUS0.000008
95. c.1188G>T p.W396Cmissense 1VUS0.000000
96. c.3335G>A p.W1112Xnonsense 1Pathogenic0.000000
97. c.2459G>A p.R820Qmissense 1Likely Pathogenic0.000016
98. c.931T>A p.S311Tmissense 1VUS0.000000
99. c.1540A>G p.I514Vmissense 1VUS0.000008
100. c.3676C>T p.R1226Cmissense 1VUS0.000058
101. c.1358C>T p.P453Lmissense 1VUS0.000008
102. c.3049G>A p.E1017Kmissense 1VUS favour benign0.000085
103. c.2938C>T p.R980Cmissense 1VUS0.000062
104. c.2170C>T p.R724Wmissense 1VUS0.000019
105. c.1294G>A p.A432Tmissense 1VUS0.000037
106. c.3G>C p.Met1?missense 1Likely Pathogenic0.000000
107. c.2557G>A p.G853Smissense 1VUS0.000008
108. c.3811C>T p.R1271Xnonsense 1Pathogenic0.000025
109. c.3040delC p.Leu1014TrpfsX6frameshift 1Pathogenic0.000000
110. c.655-1G>A essential splice site 1Pathogenic0.000000
111. c.2737+2T>A essential splice site 1Pathogenic0.000000
112. c.2993A>G p.Q998Rmissense 1VUS favour pathogenic0.000000
113. c.3605G>A p.C1202Ymissense 1Likely Pathogenic0.000000
114. c.613C>T p.Q205Xnonsense 1Pathogenic0.000000
115. c.3776delA frameshift 1Pathogenic0.000000
116. c.1213A>G p.M405Vmissense 1Pathogenic0.000000
117. c.3332_3335dupAGTG p.W1112Xnonsense 1Pathogenic0.000000
118. c.1841A>G p.Y614Cmissense 1VUS favour pathogenic0.000000
119. c.2671C>T p.R891Wmissense 1Likely Pathogenic0.000031
120. c.2953A>T p.K985Xnonsense 1Pathogenic0.000000
121. c.2641G>A p.V881Imissense 1VUS0.000018
122. c.2939G>A p.R980Hmissense 1VUS0.000000
123. c.1535T>A p.L512Qmissense 1VUS favour pathogenic0.000000
124. c.3815-1G>A essential splice site 1Pathogenic0.000000
125. c.1892delT frameshift 1Pathogenic0.000000
126. c.2449C>T p.R817Wmissense 1VUS0.000000
127. c.3753T>G p.Y1251Xnonsense 1Pathogenic0.000000
128. c.3742G>A p.G1248Rmissense 1VUS0.000033
129. c.518C>A p.T173Nmissense 1VUS0.000000
130. c.1950C>G p.D650Emissense 1VUS0.000000
131. c.2654C>T p.T885Mmissense 1VUS0.000022
132. c.2308+1G>A essential splice site 1Pathogenic0.000000
133. c.103C>T p.R35Wmissense 1VUS0.000056
134. c.2737+1G>C essential splice site 1Pathogenic0.000000
135. c.3277G>T p.G1093Cmissense 1VUS0.000020
136. c.2048G>A p.W683Xnonsense 1Pathogenic0.000000
137. c.3286G>T p.E1096Xnonsense 1Pathogenic0.000000
138. c.2308+1G>T essential splice site 1Pathogenic0.000000
139. c.3791G>A p.C1264Ymissense 1VUS0.000008
140. c.1678delG p.Asp560ThrfsX19frameshift 1Pathogenic0.000000
141. c.2556_2557delinsTCT p.Gly853fsframeshift 1Pathogenic0.000000
142. c.2149-1G>A essential splice site 1Pathogenic0.000000
143. c.821+1G>C essential splice site 1Pathogenic0.000000
144. c.3288delG frameshift 1Pathogenic0.000000
145. c.1156G>T p.E386Xnonsense 1Pathogenic0.000000
146. c.333_334insT p.E112Xnonsense 1Pathogenic0.000000
147. c.2906-2A>G essential splice site 1Pathogenic0.000000
148. c.533delT p.Val178GlyfsX7frameshift 1Pathogenic0.000000
149. c.2524_2525insT p.Tyr842LeufsX42frameshift 1Pathogenic0.000000
150. c.2610_2611insC p.Ser871GlnfsX13frameshift 1Pathogenic0.000000
151. c.1628delA frameshift 1Pathogenic0.000000
152. c.3065G>A p.R1022Hmissense 1VUS favour pathogenic0.000000
153. c.1090+1G>A essential splice site 1Pathogenic0.000000
154. c.833delG p.Gly278GlufsX22frameshift 1Pathogenic0.000000
155. c.853G>A p.D285Nmissense 1VUS0.000000
156. c.3694A>T p.K1232Xnonsense 1Pathogenic0.000000
157. c.3281A>T p.N1094Imissense 1VUS0.000000
158. c.1778C>T p.S593Fmissense 1VUS favour pathogenic0.000034
159. c.1418T>C p.F473Smissense 1VUS0.000000
160. c.1672G>A p.A558Tmissense 1VUS0.000008
161. c.2312T>C p.V771Amissense 1VUS0.000000
162. c.3373G>A p.V1125Mmissense 1VUS favour pathogenic0.000022
163. c.2518G>A p.V840Mmissense 1VUS0.000016
164. c.3413G>C p.R1138Pmissense 1VUS0.000000
165. c.3415G>A p.V1139Imissense 1VUS0.000087
166. c.2210C>T p.T737Mmissense 1VUS0.000050
167. c.373G>T p.A125Smissense 1VUS0.000000
168. c.2534_2538delGCGTC frameshift 1Pathogenic0.000000
169. c.3083C>G p.T1028Smissense 1VUS0.000000
170. c.1999_2000delinsG p.Leu667AspfsX15frameshift 1Pathogenic0.000000
171. c.1693A>T p.K565Xnonsense 1Pathogenic0.000000
172. c.3065G>C p.R1022Pmissense 1VUS favour pathogenic0.000025
173. c.1000G>T p.E334Xnonsense 1Pathogenic0.000000
174. c.844C>T p.R282Wmissense 1VUS favour pathogenic0.000000
175. c.2723A>G p.Y908Cmissense 1VUS0.000062
176. c.1699_1700delGA p.Glu567GlyfsX4frameshift 1Pathogenic0.000000
177. c.1038_1042dupCGGCA frameshift 1Pathogenic0.000008
178. c.2394_2395insT p.Gly799TrpfsX34frameshift 1Pathogenic0.000000
179. c.3166_3167insG p.Ala1056GlyfsX9frameshift 1Pathogenic0.000000
180. c.1591G>C p.G531Rmissense 1VUS favour pathogenic0.000017
181. c.1575T>G p.Y525Xnonsense 1Pathogenic0.000000
182. c.2747G>A p.W916Xnonsense 1Pathogenic0.000000
183. c.3408C>A p.Y1136Xnonsense 1Pathogenic0.000000
184. c.2533C>T p.R845Cmissense 1VUS favour pathogenic0.000000
185. c.3735delC frameshift 1Likely Pathogenic0.000000
186. c.2965G>T p.E989Xnonsense 1Pathogenic0.000000
187. c.2490_2491insT p.His831SerfsTer2frameshift 1Pathogenic0.000024
188. c.821+2T>C essential splice site 1Pathogenic0.000000
189. c.2163delC p.Glu722ArgfsX32frameshift 1Pathogenic0.000000
190. c.1224-2A>G essential splice site 1Pathogenic0.000000
191. c.3476_3479dupTTAT p.Pro1161TyrfsX9frameshift 1Pathogenic0.000000
192. c.2525A>G p.Y842Cmissense 1VUS0.000000
193. c.459delC frameshift 1Pathogenic0.000000
194. c.2013_2016delinsGG p.Pro672AspfsX20frameshift 1Pathogenic0.000000
195. c.3763G>A p.A1255Tmissense 1VUS favour pathogenic0.000075
196. c.431_432delGT p.Gly144AlafsX8frameshift 1Pathogenic0.000000
197. c.932C>T p.S311Lmissense 1VUS0.000000
198. c.566T>A p.V189Dmissense 1VUS0.000000
199. c.1397T>A p.M466Kmissense 1VUS0.000008
200. c.2197C>T p.R733Cmissense 1VUS0.000085
201. c.2436G>T p.K812Nmissense 1VUS0.000000
202. c.2269G>A p.V757Mmissense 1VUS0.000066
203. c.1960C>T p.R654Cmissense 1VUS favour benign0.000008
204. c.2828G>A p.R943Qmissense 1VUS0.000025
205. c.3825A>G p.X1275TrpextX77nonsense 1Likely Pathogenic0.000000
206. c.1168delC frameshift 1Pathogenic0.000000
207. c.451G>A p.D151Nmissense 1VUS0.000041
208. c.1624+2T>C essential splice site 1Pathogenic0.000000
209. c.104G>A p.R35Qmissense 1VUS0.000079
210. c.177_187del p.Glu60AlafsX49frameshift 1Pathogenic0.000000
211. c.1458-1G>A essential splice site 1Pathogenic0.000000
212. c.2541C>A p.Y847Xnonsense 1Pathogenic0.000000
213. c.3331-1G>A essential splice site 1Pathogenic0.000000
214. c.932C>A p.S311Xnonsense 1Pathogenic0.000000
215. c.1586C>G p.T529Smissense 1VUS favour pathogenic0.000000
216. c.1343T>C p.F448Smissense 1Likely Pathogenic0.000000
217. c.1924C>T p.Q642Xnonsense 1Pathogenic0.000000
218. c.551_552insT p.Lys185GlufsX56frameshift 1Pathogenic0.000000
219. c.966G>A p.W322Xnonsense 1Pathogenic0.000000
220. c.1505G>T p.R502Lmissense 1VUS favour pathogenic0.000000
221. c.3548T>G p.F1183Cmissense 1Likely Pathogenic0.000000
222. c.3181C>T p.Q1061Xnonsense 1Pathogenic0.000016
223. c.2517_2538del p.Val840ThrfsX32frameshift 1Pathogenic0.000000
224. c.223G>A p.D75Nmissense 1VUS favour pathogenic0.000091
225. c.713G>A p.R238Hmissense 1VUS0.000074
226. c.2560A>G p.M854Vmissense 1VUS0.000000
227. c.3098G>A p.R1033Qmissense 1VUS0.000000
228. c.1800delA frameshift 1Pathogenic0.000000
229. c.3746G>T p.G1249Vmissense 1VUS0.000000
230. c.2833_2834delCG frameshift 1Pathogenic0.000000
231. c.2905+1G>C essential splice site 1Pathogenic0.000000
232. c.3068_3069insA p.Asn1023LysfsX28frameshift 1Pathogenic0.000000
233. c.2113_2114insA p.Thr705AsnfsX3frameshift 1Pathogenic0.000000
234. c.1351+2T>C essential splice site 1Pathogenic0.000000
235. c.1273C>T p.Q425Xnonsense 1Pathogenic0.000000
236. c.3600_3609delCTGCTGTGCT frameshift 0Pathogenic0.000000


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.