MYBPC3 variants in HCM cohorts


The table below lists the 636 rare (MAF<0.0001 in ExAC) protein-altering MYBPC3 variants identified in a cohort of 3267 HCM patients. When this rare variant frequency of 0.19467 is compared with a background population rate of 0.01970, there is a statistically significant case excess of 0.17497 (p<0.0001), which suggests that approximately 572 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 (3267)OMGL class ExAC frequency
1. c.1504C>T p.R502Wmissense 59Pathogenic0.000024
2. c.772G>A p.E258Kmissense 47Pathogenic0.000039
3. c.2373_2374insG p.Trp792ValfsTer41frameshift 40Pathogenic0.000037
4. c.1624G>C p.E542Qmissense 24Pathogenic0.000024
5. c.655G>C p.V219Lmissense 18Likely Pathogenic0.000000
6. c.2096delC frameshift 15Pathogenic0.000000
7. c.3226_3227insT frameshift 12Pathogenic0.000000
8. c.2827C>T p.R943Xnonsense 11Pathogenic0.000017
9. c.2429G>A p.R810Hmissense 11VUS0.000033
10. c.1483C>G p.R495Gmissense 10Likely Pathogenic0.000000
11. c.1928-2A>G essential splice site 10Pathogenic0.000000
12. c.3613C>T p.R1205Wmissense 10Likely Pathogenic0.000016
13. c.3771C>A p.N1257Kmissense 9Likely Pathogenic0.000000
14. c.927-2A>G essential splice site 8Pathogenic0.000000
15. c.2864_2865delCT frameshift 8Pathogenic0.000000
16. c.2604_2605delinsA p.S871fsframeshift 8Pathogenic0.000000
17. c.2490_2491insT p.His831SerfsTer2frameshift 7Pathogenic0.000024
18. c.3190+2T>G essential splice site 7Pathogenic0.000016
19. c.3627+1G>A essential splice site 6Pathogenic0.000000
20. c.3065G>C p.R1022Pmissense 5Likely Pathogenic0.000025
21. c.2308G>A p.D770Nmissense 5Likely Pathogenic0.000008
22. c.2459G>A p.R820Qmissense 5VUS0.000016
23. c.2610delC frameshift 5Pathogenic0.000000
24. c.2267delC frameshift 5Pathogenic0.000000
25. c.2556_2557delinsTCT p.Gly853fsframeshift 4Pathogenic0.000000
26. c.1484G>A p.R495Qmissense 4Likely Pathogenic0.000008
27. c.821+2T>C essential splice site 4Pathogenic0.000000
28. c.442G>A p.G148Rmissense 4Likely Pathogenic0.000042
29. c.3798C>G p.C1266Wmissense 4VUS0.000000
30. c.3163A>T p.K1055Xnonsense 4Pathogenic0.000000
31. c.484C>T p.Q162Xnonsense 4Pathogenic0.000000
32. c.3697C>T p.Q1233Xnonsense 4Likely Pathogenic0.000008
33. c.3763G>A p.A1255Tmissense 3VUS0.000075
34. c.3408C>A p.Y1136Xnonsense 3Pathogenic0.000000
35. c.3600_3609delCTGCTGTGCT frameshift 3Pathogenic0.000000
36. c.2545del p.Val849Serfs*30frameshift 3Pathogenic0.000000
37. c.3277G>T p.G1093Cmissense 3VUS0.000020
38. c.710A>C p.Y237Smissense 3Likely Pathogenic0.000000
39. c.3181C>T p.Q1061Xnonsense 3Pathogenic0.000016
40. c.1720C>T p.R574Wmissense 3VUS0.000054
41. c.3286G>T p.E1096Xnonsense 3Pathogenic0.000000
42. c.2210C>T p.T737Mmissense 3VUS0.000050
43. c.3129C>A p.Y1043Xnonsense 3Pathogenic0.000000
44. c.2309-1G>A essential splice site 3Pathogenic0.000000
45. c.2905+1G>A essential splice site 3Pathogenic0.000000
46. c.1123G>A p.V375Mmissense 3VUS0.000009
47. c.2573G>A p.S858Nmissense 2Likely Pathogenic0.000000
48. c.443dup p.Ala149Serfs*4frameshift 2Pathogenic0.000000
49. c.818G>A p.R273Hmissense 2VUS0.000042
50. c.3470C>T p.P1157Lmissense 2VUS0.000093
51. c.2905C>T p.Q969Xnonsense 2Pathogenic0.000000
52. c.1828G>A p.D610Nmissense 2VUS0.000000
53. c.2432A>G p.K811Rmissense 2VUS0.000000
54. c.747C>A p.C249Xnonsense 2Pathogenic0.000000
55. c.25+1G>A essential splice site 2Pathogenic0.000000
56. c.1505G>A p.R502Qmissense 2Pathogenic0.000000
57. c.3005G>A p.R1002Qmissense 2VUS0.000046
58. c.3627+1G>T essential splice site 2Pathogenic0.000000
59. c.3752A>G p.Y1251Cmissense 2VUS0.000000
60. c.2905+2dup essential splice site 2Likely Pathogenic0.000000
61. c.2524dup p.Tyr842Leufs*42frameshift 2Pathogenic0.000000
62. c.2300A>G p.K767Rmissense 2VUS0.000016
63. c.1483C>T p.R495Wmissense 2Likely Pathogenic0.000000
64. c.557C>T p.P186Lmissense 2VUS0.000047
65. c.3271del p.Asp1091Metfs*98frameshift 2Pathogenic0.000000
66. c.177_187del p.Glu60AlafsX49frameshift 2Pathogenic0.000000
67. c.3455_3466del p.Ala1152_Lys1155delinframe 2Likely Pathogenic0.000000
68. c.2308+1G>A essential splice site 2Pathogenic0.000000
69. c.2219G>C p.G740Amissense 2VUS0.000000
70. c.3751T>C p.Y1251Hmissense 2VUS0.000000
71. c.3582_3593delGGGCTACACTGC inframe 2Likely Pathogenic0.000000
72. c.1886T>C p.L629Pmissense 2VUS0.000000
73. c.2526C>G p.Y842Xnonsense 2Pathogenic0.000000
74. c.126G>A p.W42Xnonsense 2Pathogenic0.000000
75. c.833delG p.Gly278GlufsX22frameshift 2Pathogenic0.000000
76. c.146_148delTCA p.Ile49delinframe 1VUS0.000039
77. c.799C>G p.L267Vmissense 1VUS0.000080
78. c.459delC frameshift 1Pathogenic0.000000
79. c.3253G>T p.E1085Xnonsense 1Pathogenic0.000000
80. c.3364A>T p.T1122Smissense 1Likely Pathogenic0.000000
81. c.3656T>C p.L1219Pmissense 1VUS0.000000
82. c.3792_3793del p.Cys1264*frameshift 1Likely Pathogenic0.000000
83. c.3256T>C p.W1086Rmissense 1VUS0.000000
84. c.187C>T p.R63Wmissense 1VUS0.000077
85. c.2953A>G p.K985Emissense 1Pathogenic0.000000
86. c.3297dup p.Tyr1100Valfs*49frameshift 1Pathogenic0.000000
87. c.2149_2737del p.Leu717Alafs*11frameshift 1Pathogenic0.000000
88. c.2188del p.Thr730Profs*24frameshift 1Pathogenic0.000000
89. c.1404del p.Gln469Serfs*19frameshift 1Pathogenic0.000000
90. c.2198G>A p.R733Hmissense 1VUS0.000034
91. c.1731G>C p.W577Cmissense 1VUS0.000000
92. c.1624+1G>A essential splice site 1Pathogenic0.000000
93. c.1090+2T>C essential splice site 1Pathogenic0.000000
94. c.2249C>T p.T750Mmissense 1Likely Pathogenic0.000024
95. c.365C>A p.A122Dmissense 1VUS0.000000
96. c.1231A>G p.I411Vmissense 1VUS0.000000
97. c.701C>A p.T234Nmissense 1Likely Pathogenic0.000000
98. c.1999_2000delinsG p.Leu667AspfsX15frameshift 1Pathogenic0.000000
99. c.1455A>T p.K485Nmissense 1VUS0.000000
100. c.1037G>A p.R346Hmissense 1VUS0.000000
101. c.1213A>G p.M405Vmissense 1VUS0.000000
102. c.211_212delinsTA p.Val71*frameshift 1Pathogenic0.000000
103. c.1377delC frameshift 1Pathogenic0.000000
104. c.532G>A p.V178Mmissense 1VUS0.000020
105. c.3811C>T p.R1271Xnonsense 1VUS0.000025
106. c.1090+1G>A essential splice site 1Pathogenic0.000000
107. c.*26+2T>C essential splice site 1Likely Pathogenic0.000000
108. c.3614G>A p.R1205Qmissense 1VUS0.000016
109. c.188G>A p.R63Qmissense 1VUS0.000039
110. c.3614G>C p.R1205Pmissense 1Likely Pathogenic0.000000
111. c.2748G>A p.W916Xnonsense 1Pathogenic0.000000
112. c.3316G>A p.D1106Nmissense 1VUS0.000061
113. c.3739G>A p.D1247Nmissense 1VUS0.000000
114. c.3043dup p.Ala1015Glyfs*36frameshift 1Pathogenic0.000000
115. c.3572C>T p.S1191Lmissense 1VUS0.000016
116. c.2603-1G>C essential splice site 1Pathogenic0.000000
117. c.3330+1G>C essential splice site 1Pathogenic0.000000
118. c.1797del p.His599Glnfs*3frameshift 1Pathogenic0.000000
119. c.2690_2696del p.Gly897Glufs*25frameshift 1Pathogenic0.000000
120. c.2304_2308+2delCATCGGT essential splice site 1Pathogenic0.000000
121. c.2247C>A p.Y749Xnonsense 1Pathogenic0.000000
122. c.2504G>T p.R835Lmissense 1Likely Pathogenic0.000074
123. c.2429_2503delins23 p.Arg810Profs*10frameshift 1Pathogenic0.000000
124. c.1352_1353del p.Glu451Alafs*23frameshift 1Pathogenic0.000000
125. c.2030C>T p.P677Lmissense 1VUS0.000000
126. c.1458G>A p.W486Xnonsense 1Pathogenic0.000000
127. c.1120C>T p.Q374Xnonsense 1Pathogenic0.000000
128. c.2065C>T p.Q689Xnonsense 1Pathogenic0.000000
129. c.255del p.Ser86Profs*10frameshift 1Pathogenic0.000000
130. c.1456T>G p.W486Gmissense 1VUS0.000000
131. c.553_562del p.Lys185Trpfs*12frameshift 1Pathogenic0.000000
132. c.1021_1028del p.Gly341*frameshift 1Pathogenic0.000000
133. c.743_746delACTG frameshift 1Pathogenic0.000000
134. c.1112C>T p.P371Lmissense 1VUS0.000028
135. c.121dup p.Arg41Profs*8frameshift 1Pathogenic0.000000
136. c.1303C>T p.Q435Xnonsense 1Pathogenic0.000000
137. c.994G>A p.E332Kmissense 1VUS0.000009
138. c.3713T>C p.L1238Pmissense 1Likely Pathogenic0.000000
139. c.148A>G p.S50Gmissense 1VUS0.000038
140. c.772+1G>A essential splice site 1Pathogenic0.000000
141. c.3624delC frameshift 1Pathogenic0.000000
142. c.3206C>A p.P1069Hmissense 1Likely Pathogenic0.000000
143. c.3605delG frameshift 1Pathogenic0.000000
144. c.3357C>A p.Y1119Xnonsense 1Pathogenic0.000000
145. c.2807dup p.Ala938Glyfs*113frameshift 1Pathogenic0.000000
146. c.2371C>T p.Q791Xnonsense 1Pathogenic0.000000
147. c.2909G>A p.R970Qmissense 1Likely Pathogenic0.000032
148. c.2534_2538delGCGTC frameshift 1Pathogenic0.000000
149. c.3064C>T p.R1022Cmissense 1VUS0.000008
150. c.2718_2719dup p.Glu907Glyfs*18frameshift 1Pathogenic0.000000
151. c.2558delG frameshift 1Pathogenic0.000000
152. c.1201C>T p.Q401Xnonsense 1Pathogenic0.000000
153. c.2161_2168del p.Thr721Profs*23frameshift 1Pathogenic0.000000
154. c.1841A>G p.Y614Cmissense 1VUS0.000000
155. c.1376_1377del p.Pro459Leufs*15frameshift 1Pathogenic0.000000
156. c.2449C>T p.R817Wmissense 1VUS0.000000
157. c.2381C>A p.P794Qmissense 1VUS0.000000
158. c.2197C>T p.R733Cmissense 1Likely Pathogenic0.000085
159. c.1569dup p.His524Alafs*7frameshift 1Pathogenic0.000000
160. c.1471G>A p.V491Mmissense 1VUS0.000058
161. c.655-2del essential splice site 1Pathogenic0.000000
162. c.1080G>C p.K360Nmissense 1VUS0.000000
163. c.351_352del p.Gly118Argfs*8frameshift 1Pathogenic0.000000
164. c.1790G>A p.R597Qmissense 1VUS0.000000
165. c.1224-1G>T essential splice site 1Pathogenic0.000000
166. c.844C>T p.R282Wmissense 1Likely Pathogenic0.000000
167. c.1351+1G>A essential splice site 1Pathogenic0.000000
168. c.391dup p.Ala131Glyfs*22frameshift 1Pathogenic0.000000
169. c.1021G>C p.G341Rmissense 1VUS0.000000
170. c.1153G>A p.V385Mmissense 1VUS0.000010
171. c.177dup p.Glu60Argfs*53frameshift 1Pathogenic0.000000
172. c.811_817delTTCCGCC frameshift 1Pathogenic0.000000
173. c.506-1G>A essential splice site 1Pathogenic0.000000
174. c.932C>A p.S311Xnonsense 1Pathogenic0.000000
175. c.3676C>T p.R1226Cmissense 1VUS0.000058
176. c.3452C>T p.A1151Vmissense 1VUS0.000078
177. c.3257G>A p.W1086Xnonsense 1Pathogenic0.000021
178. c.2584C>T p.Q862Xnonsense 1Pathogenic0.000000
179. c.3316del p.Asp1106Thrfs*83frameshift 1Pathogenic0.000000
180. c.2738-2A>G essential splice site 1Pathogenic0.000000
181. c.2953A>T p.K985Xnonsense 1Pathogenic0.000000
182. c.2968C>G p.P990Amissense 1Likely Pathogenic0.000000
183. c.1405C>T p.Q469Xnonsense 1Pathogenic0.000000
184. c.2503C>T p.R835Cmissense 1VUS0.000024
185. c.2502del p.Arg835Alafs*2frameshift 1Pathogenic0.000000
186. c.1756C>G p.P586Amissense 1Likely Pathogenic0.000000
187. c.2603-2_2603-1delinsGA essential splice site 1Pathogenic0.000000
188. c.2873C>T p.T958Imissense 1VUS0.000065
189. c.1266_1267insTGAT p.Ile423*frameshift 1Pathogenic0.000000
190. c.731del p.Lys244Argfs*56frameshift 1Pathogenic0.000000
191. c.1457G>A p.W486Xnonsense 1Pathogenic0.000000
192. c.1685C>T p.A562Vmissense 1VUS0.000008
193. c.1097A>C p.Q366Pmissense 1VUS0.000000
194. c.2265C>A p.N755Kmissense 1Pathogenic0.000000
195. c.1A>T p.Met1?missense 1Likely Pathogenic0.000000
196. c.821+2T>G essential splice site 1Pathogenic0.000000
197. c.1273C>T p.Q425Xnonsense 1Pathogenic0.000000
198. c.241G>T p.V81Fmissense 1VUS0.000000
199. c.1433C>T p.S478Lmissense 1Likely Pathogenic0.000017
200. c.1072G>A p.D358Nmissense 1VUS0.000008
201. c.982delG frameshift 1Pathogenic0.000000
202. c.711C>A p.Y237Xnonsense 1Pathogenic0.000000
203. c.1090+1G>T essential splice site 1Pathogenic0.000000
204. c.821+1G>A essential splice site 1Pathogenic0.000043
205. c.3617delG frameshift 1Pathogenic0.000000
206. c.373G>T p.A125Smissense 1VUS0.000000
207. c.3728C>G p.P1243Rmissense 1VUS0.000000
208. c.631G>A p.D211Nmissense 1VUS0.000009
209. c.3490+1G>A essential splice site 1Pathogenic0.000000
210. c.49C>T p.R17Wmissense 1VUS0.000023
211. c.3373G>A p.V1125Mmissense 1VUS0.000022
212. c.2995-1G>A essential splice site 1Pathogenic0.000000
213. c.3334_3351del p.Trp1112_Glu1117delinframe 1Likely Pathogenic0.000000
214. c.2789del p.Leu930Argfs*2frameshift 1Pathogenic0.000000
215. c.2708G>A p.G903Dmissense 1Likely Pathogenic0.000000
216. c.2834G>A p.R945Qmissense 1VUS0.000000
217. c.2512dup p.Glu838Glyfs*46frameshift 1Pathogenic0.000000
218. c.3019T>C p.W1007Rmissense 1VUS0.000000
219. c.1523_1525delinsT p.Gln508Leufs*22frameshift 1Pathogenic0.000000
220. c.1174G>T p.A392Smissense 1VUS0.000000
221. c.2269G>A p.V757Mmissense 1VUS0.000066
222. c.2054_2067+11del p.Lys685Argfs*3frameshift 1Pathogenic0.000000
223. c.1828G>C p.D610Hmissense 1VUS0.000058
224. c.1359del p.Val454Cysfs*12frameshift 1Pathogenic0.000000
225. c.1223+2T>C essential splice site 1Pathogenic0.000000
226. c.611_618delinsT p.Gly204Valfs*94frameshift 1Pathogenic0.000000
227. c.1898-1G>A essential splice site 1Pathogenic0.000000
228. c.100_110dup p.Val38Serfs*5frameshift 1Pathogenic0.000000
229. c.1591G>A p.G531Rmissense 1Likely Pathogenic0.000017
230. c.1038_1042dupCGGCA frameshift 1Pathogenic0.000008
231. c.1291G>A p.D431Nmissense 1VUS0.000028
232. c.256_258del p.Ser86delinframe 1VUS0.000000
233. c.1789C>T p.R597Wmissense 1VUS0.000038
234. c.1021G>A p.G341Smissense 1VUS0.000025

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.