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