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

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.