MYBPC3 protein-altering 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.1484G>A p.R495Qmissense 10VUS favour pathogenic0.000008
2. c.3746G>T p.G1249Vmissense 1VUS0.000000
3. c.3098G>A p.R1033Qmissense 1VUS0.000000
4. c.2320G>A p.A774Tmissense 2VUS0.000000
5. c.636C>G p.S212Rmissense 2VUS favour pathogenic0.000000
6. c.1456T>G p.W486Gmissense 1Likely Pathogenic0.000000
7. c.1504C>T p.R502Wmissense 45Pathogenic0.000024
8. c.290C>T p.A97Vmissense 1VUS favour pathogenic0.000000
9. c.3797G>A p.C1266Ymissense 1Likely Pathogenic0.000000
10. c.3580G>A p.A1194Tmissense 1VUS0.000008
11. c.1188G>T p.W396Cmissense 1VUS0.000000
12. c.436A>C p.T146Pmissense 1VUS0.000000
13. c.481C>A p.P161Tmissense 1VUS favour pathogenic0.000041
14. c.2234A>G p.D745Gmissense 1VUS0.000000
15. c.326C>T p.A109Vmissense 1VUS0.000000
16. c.1021G>A p.G341Smissense 1VUS favour pathogenic0.000025
17. c.1828G>C p.D610Hmissense 2VUS favour benign0.000058
18. c.931T>A p.S311Tmissense 1VUS0.000000
19. c.1540A>G p.I514Vmissense 1VUS0.000008
20. c.2873C>T p.T958Imissense 3VUS favour benign0.000065
21. c.1483C>G p.R495Gmissense 4Likely Pathogenic0.000000
22. c.3049G>A p.E1017Kmissense 1VUS favour benign0.000085
23. c.2938C>T p.R980Cmissense 1VUS0.000062
24. c.2170C>T p.R724Wmissense 1VUS0.000019
25. c.3676C>T p.R1226Cmissense 1VUS0.000058
26. c.1358C>T p.P453Lmissense 1VUS0.000008
27. c.1294G>A p.A432Tmissense 1VUS0.000037
28. c.3G>C p.Met1?missense 1Likely Pathogenic0.000000
29. c.2557G>A p.G853Smissense 1VUS0.000008
30. c.2993A>G p.Q998Rmissense 1VUS favour pathogenic0.000000
31. c.3605G>A p.C1202Ymissense 1Likely Pathogenic0.000000
32. c.2374T>C p.W792Rmissense 5Likely Pathogenic0.000000
33. c.1591G>A p.G531Rmissense 3VUS favour pathogenic0.000017
34. c.1213A>G p.M405Vmissense 1Pathogenic0.000000
35. c.1841A>G p.Y614Cmissense 1VUS favour pathogenic0.000000
36. c.2671C>T p.R891Wmissense 1Likely Pathogenic0.000031
37. c.3064C>T p.R1022Cmissense 4VUS favour pathogenic0.000008
38. c.2449C>T p.R817Wmissense 1VUS0.000000
39. c.2641G>A p.V881Imissense 1VUS0.000018
40. c.2939G>A p.R980Hmissense 1VUS0.000000
41. c.1535T>A p.L512Qmissense 1VUS favour pathogenic0.000000
42. c.3742G>A p.G1248Rmissense 1VUS0.000033
43. c.518C>A p.T173Nmissense 1VUS0.000000
44. c.1950C>G p.D650Emissense 1VUS0.000000
45. c.103C>T p.R35Wmissense 1VUS0.000056
46. c.2654C>T p.T885Mmissense 1VUS0.000022
47. c.3373G>A p.V1125Mmissense 1VUS favour pathogenic0.000022
48. c.1828G>A p.D610Nmissense 3VUS0.000000
49. c.3791G>A p.C1264Ymissense 1VUS0.000008
50. c.3277G>T p.G1093Cmissense 1VUS0.000020
51. c.710A>C p.Y237Smissense 3Likely Pathogenic0.000000
52. c.2429G>A p.R810Hmissense 8VUS favour pathogenic0.000033
53. c.1483C>T p.R495Wmissense 2VUS favour pathogenic0.000000
54. c.1790G>A p.R597Qmissense 2VUS favour pathogenic0.000000
55. c.3065G>A p.R1022Hmissense 1VUS favour pathogenic0.000000
56. c.2450G>A p.R817Qmissense 3VUS favour pathogenic0.000016
57. c.1766G>A p.R589Hmissense 2VUS0.000000
58. c.3281A>T p.N1094Imissense 1VUS0.000000
59. c.1778C>T p.S593Fmissense 1VUS favour pathogenic0.000034
60. c.1418T>C p.F473Smissense 1VUS0.000000
61. c.853G>A p.D285Nmissense 1VUS0.000000
62. c.2518G>A p.V840Mmissense 1VUS0.000016
63. c.3413G>C p.R1138Pmissense 1VUS0.000000
64. c.2308G>A p.D770Nmissense 6Likely Pathogenic0.000008
65. c.1672G>A p.A558Tmissense 1VUS0.000008
66. c.2312T>C p.V771Amissense 1VUS0.000000
67. c.1505G>A p.R502Qmissense 6Pathogenic0.000000
68. c.3083C>G p.T1028Smissense 1VUS0.000000
69. c.3415G>A p.V1139Imissense 1VUS0.000087
70. c.2210C>T p.T737Mmissense 1VUS0.000050
71. c.373G>T p.A125Smissense 1VUS0.000000
72. c.3065G>C p.R1022Pmissense 1VUS favour pathogenic0.000025
73. c.844C>T p.R282Wmissense 1VUS favour pathogenic0.000000
74. c.2723A>G p.Y908Cmissense 1VUS0.000062
75. c.772G>A p.E258Kmissense 21Pathogenic0.000039
76. c.1591G>C p.G531Rmissense 1VUS favour pathogenic0.000017
77. c.2533C>T p.R845Cmissense 1VUS favour pathogenic0.000000
78. c.442G>A p.G148Rmissense 7VUS favour pathogenic0.000042
79. c.1037G>A p.R346Hmissense 2VUS0.000000
80. c.3763G>A p.A1255Tmissense 1VUS favour pathogenic0.000075
81. c.2525A>G p.Y842Cmissense 1VUS0.000000
82. c.2882C>T p.P961Lmissense 2VUS0.000048
83. c.1397T>A p.M466Kmissense 1VUS0.000008
84. c.2197C>T p.R733Cmissense 1VUS0.000085
85. c.2436G>T p.K812Nmissense 1VUS0.000000
86. c.2269G>A p.V757Mmissense 1VUS0.000066
87. c.1960C>T p.R654Cmissense 1VUS favour benign0.000008
88. c.932C>T p.S311Lmissense 1VUS0.000000
89. c.566T>A p.V189Dmissense 1VUS0.000000
90. c.1624G>C p.E542Qmissense 17Likely Pathogenic0.000024
91. c.2828G>A p.R943Qmissense 1VUS0.000025
92. c.104G>A p.R35Qmissense 1VUS0.000079
93. c.451G>A p.D151Nmissense 1VUS0.000041
94. c.655G>C p.V219Lmissense 8Likely Pathogenic0.000000
95. c.2573G>A p.S858Nmissense 4VUS favour pathogenic0.000000
96. c.1586C>G p.T529Smissense 1VUS favour pathogenic0.000000
97. c.1343T>C p.F448Smissense 1Likely Pathogenic0.000000
98. c.532G>A p.V178Mmissense 2VUS favour pathogenic0.000020
99. c.3548T>G p.F1183Cmissense 1Likely Pathogenic0.000000
100. c.1505G>T p.R502Lmissense 1VUS favour pathogenic0.000000
101. c.814C>T p.R272Cmissense 2VUS0.000083
102. c.355G>A p.E119Kmissense 3VUS0.000000
103. c.223G>A p.D75Nmissense 1VUS favour pathogenic0.000091
104. c.1934C>T p.P645Lmissense 2VUS0.000000
105. c.713G>A p.R238Hmissense 1VUS0.000074
106. c.2560A>G p.M854Vmissense 1VUS0.000000
107. c.2459G>A p.R820Qmissense 1Likely Pathogenic0.000016
108. c.1273C>T p.Q425Xnonsense 1Pathogenic0.000000
109. c.2437A>T p.K813Xnonsense 1Pathogenic0.000000
110. c.3253G>T p.E1085Xnonsense 1Pathogenic0.000000
111. c.993_994insT p.E332Xnonsense 1Pathogenic0.000000
112. c.3335G>A p.W1112Xnonsense 1Pathogenic0.000000
113. c.3811C>T p.R1271Xnonsense 1Pathogenic0.000025
114. c.3332_3335dupAGTG p.W1112Xnonsense 1Pathogenic0.000000
115. c.2953A>T p.K985Xnonsense 1Pathogenic0.000000
116. c.2454G>A p.W818Xnonsense 4Pathogenic0.000000
117. c.613C>T p.Q205Xnonsense 1Pathogenic0.000000
118. c.3753T>G p.Y1251Xnonsense 1Pathogenic0.000000
119. c.2905C>T p.Q969Xnonsense 3Pathogenic0.000000
120. c.2048G>A p.W683Xnonsense 1Pathogenic0.000000
121. c.3286G>T p.E1096Xnonsense 1Pathogenic0.000000
122. c.2670G>A p.W890Xnonsense 7Pathogenic0.000000
123. c.1156G>T p.E386Xnonsense 1Pathogenic0.000000
124. c.333_334insT p.E112Xnonsense 1Pathogenic0.000000
125. c.999C>G p.Y333Xnonsense 2Pathogenic0.000000
126. c.3694A>T p.K1232Xnonsense 1Pathogenic0.000000
127. c.1000G>T p.E334Xnonsense 1Pathogenic0.000000
128. c.1693A>T p.K565Xnonsense 1Pathogenic0.000000
129. c.1575T>G p.Y525Xnonsense 1Pathogenic0.000000
130. c.2747G>A p.W916Xnonsense 1Pathogenic0.000000
131. c.3408C>A p.Y1136Xnonsense 1Pathogenic0.000000
132. c.2965G>T p.E989Xnonsense 1Pathogenic0.000000
133. c.3233G>A p.W1078Xnonsense 3Pathogenic0.000022
134. c.3825A>G p.X1275TrpextX77nonsense 1Likely Pathogenic0.000000
135. c.2827C>T p.R943Xnonsense 7Pathogenic0.000017
136. c.2182G>T p.E728Xnonsense 4Pathogenic0.000000
137. c.3697C>T p.Q1233Xnonsense 9Pathogenic0.000008
138. c.2920C>T p.Q974Xnonsense 3Pathogenic0.000000
139. c.1924C>T p.Q642Xnonsense 1Pathogenic0.000000
140. c.2541C>A p.Y847Xnonsense 1Pathogenic0.000000
141. c.1210C>T p.Q404Xnonsense 2Pathogenic0.000000
142. c.932C>A p.S311Xnonsense 1Pathogenic0.000000
143. c.966G>A p.W322Xnonsense 1Pathogenic0.000000
144. c.1869C>A p.C623Xnonsense 2Pathogenic0.000000
145. c.3181C>T p.Q1061Xnonsense 1Pathogenic0.000016
146. c.2905+1G>C essential splice site 1Pathogenic0.000000
147. c.1928-2A>G essential splice site 20Pathogenic0.000000
148. c.1351+2T>C essential splice site 1Pathogenic0.000000
149. c.26-2A>G essential splice site 4Pathogenic0.000051
150. c.1090+1G>T essential splice site 1Pathogenic0.000000
151. c.1897+1G>A essential splice site 2Pathogenic0.000000
152. c.1351+1G>A essential splice site 1Pathogenic0.000000
153. c.3491-2A>T essential splice site 3Pathogenic0.000000
154. c.506-1G>T essential splice site 1Pathogenic0.000000
155. c.2308+1G>A essential splice site 1Pathogenic0.000000
156. c.821+1G>A essential splice site 4Pathogenic0.000043
157. c.2309-2A>G essential splice site 9Pathogenic0.000000
158. c.3627+1G>A essential splice site 2Pathogenic0.000000
159. c.2905+1G>A essential splice site 4Pathogenic0.000000
160. c.655-1G>A essential splice site 1Pathogenic0.000000
161. c.2737+2T>A essential splice site 1Pathogenic0.000000
162. c.3815-1G>A essential splice site 1Pathogenic0.000000
163. c.2737+1G>C essential splice site 1Pathogenic0.000000
164. c.2149-1G>A essential splice site 1Pathogenic0.000000
165. c.821+1G>C essential splice site 1Pathogenic0.000000
166. c.3330+2T>G essential splice site 11Pathogenic0.000000
167. c.2906-2A>G essential splice site 1Pathogenic0.000000
168. c.1090+1G>A essential splice site 1Pathogenic0.000000
169. c.3190+1G>A essential splice site 3Pathogenic0.000000
170. c.927-2A>G essential splice site 2Pathogenic0.000000
171. c.1224-2A>G essential splice site 1Pathogenic0.000000
172. c.821+2T>C essential splice site 1Pathogenic0.000000
173. c.2308+1G>T essential splice site 1Pathogenic0.000000
174. c.1624+2T>C essential splice site 1Pathogenic0.000000
175. c.772+1G>A essential splice site 2Pathogenic0.000000
176. c.1458-1G>A essential splice site 1Pathogenic0.000000
177. c.3331-1G>A essential splice site 1Pathogenic0.000000
178. c.3190+2T>G essential splice site 2Pathogenic0.000016
179. c.2096delC frameshift 4Pathogenic0.000000
180. c.1800delA frameshift 1Pathogenic0.000000
181. c.3068_3069insA p.Asn1023LysfsX28frameshift 1Pathogenic0.000000
182. c.2113_2114insA p.Thr705AsnfsX3frameshift 1Pathogenic0.000000
183. c.3690_3691delCA p.Phe1230LeufsX11frameshift 1Pathogenic0.000000
184. c.2875_2876delAC p.Thr959GlyfsX91frameshift 1Pathogenic0.000000
185. c.2780_2781delCA frameshift 1Pathogenic0.000000
186. c.3476_3477delTT frameshift 1Pathogenic0.000000
187. c.2040_2041insT p.Val681CysfsX12frameshift 1Pathogenic0.000000
188. c.1357_1358delCC frameshift 2Pathogenic0.000000
189. c.2311_2312insG p.Val771GlyfsX62frameshift 3Pathogenic0.000000
190. c.3040delC p.Leu1014TrpfsX6frameshift 1Pathogenic0.000000
191. c.1863delC p.Phe621LeufsX42frameshift 2Pathogenic0.000000
192. c.3776delA frameshift 1Pathogenic0.000000
193. c.1892delT frameshift 1Pathogenic0.000000
194. c.3226_3227insT frameshift 6Pathogenic0.000000
195. c.2534_2538delGCGTC frameshift 1Pathogenic0.000000
196. c.2373_2374insG p.Trp792ValfsTer41frameshift 26Pathogenic0.000037
197. c.3288delG frameshift 1Pathogenic0.000000
198. c.1678delG p.Asp560ThrfsX19frameshift 1Pathogenic0.000000
199. c.2556_2557delinsTCT p.Gly853fsframeshift 1Pathogenic0.000000
200. c.3192_3193insC p.Lys1065GlnfsX12frameshift 2Pathogenic0.000000
201. c.533delT p.Val178GlyfsX7frameshift 1Pathogenic0.000000
202. c.2524_2525insT p.Tyr842LeufsX42frameshift 1Pathogenic0.000000
203. c.833delG p.Gly278GlufsX22frameshift 1Pathogenic0.000000
204. c.2943_2947delGACCA frameshift 2Pathogenic0.000000
205. c.2610_2611insC p.Ser871GlnfsX13frameshift 1Pathogenic0.000000
206. c.1628delA frameshift 1Pathogenic0.000000
207. c.3624_3625insC p.Lys1209GlnfsX33frameshift 2Pathogenic0.000000
208. c.3600_3609delCTGCTGTGCT frameshift 0Pathogenic0.000000
209. c.2558delG frameshift 2Pathogenic0.000000
210. c.1699_1700delGA p.Glu567GlyfsX4frameshift 1Pathogenic0.000000
211. c.1999_2000delinsG p.Leu667AspfsX15frameshift 1Pathogenic0.000000
212. c.3166_3167insG p.Ala1056GlyfsX9frameshift 1Pathogenic0.000000
213. c.1895delT p.Met632ArgfsX31frameshift 2Pathogenic0.000000
214. c.1038_1042dupCGGCA frameshift 1Pathogenic0.000008
215. c.913_914delTT frameshift 5Pathogenic0.000000
216. c.2394_2395insT p.Gly799TrpfsX34frameshift 1Pathogenic0.000000
217. c.2163delC p.Glu722ArgfsX32frameshift 1Pathogenic0.000000
218. c.3476_3479dupTTAT p.Pro1161TyrfsX9frameshift 1Pathogenic0.000000
219. c.3735delC frameshift 1Likely Pathogenic0.000000
220. c.2490_2491insT p.His831SerfsTer2frameshift 1Pathogenic0.000024
221. c.431_432delGT p.Gly144AlafsX8frameshift 1Pathogenic0.000000
222. c.459delC frameshift 1Pathogenic0.000000
223. c.2013_2016delinsGG p.Pro672AspfsX20frameshift 1Pathogenic0.000000
224. c.2833_2834delCG frameshift 1Pathogenic0.000000
225. c.1168delC frameshift 1Pathogenic0.000000
226. c.2864_2865delCT frameshift 6Pathogenic0.000000
227. c.2604_2605delinsA p.S871fsframeshift 2Pathogenic0.000000
228. c.177_187del p.Glu60AlafsX49frameshift 1Pathogenic0.000000
229. c.551_552insT p.Lys185GlufsX56frameshift 1Pathogenic0.000000
230. c.3624delC frameshift 2Pathogenic0.000000
231. c.436_437insA p.Thr146AsnfsX7frameshift 2Pathogenic0.000000
232. c.2517_2538del p.Val840ThrfsX32frameshift 1Pathogenic0.000000
233. c.1513_1515delAAG inframe 2VUS favour pathogenic0.000000
234. c.2528_2536delAGATGCGCG p.Glu843_Arg845delinframe 1Pathogenic0.000000
235. c.3742_3759dup p.Gly1248_Cys1253dupinframe 4Likely Pathogenic0.000000
236. c.3767_3769delCCA p.Thr1256delinframe 3Likely Pathogenic0.000000

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.