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