MYBPC3 truncating variants in HCM cohorts


The table below lists the 566 rare (MAF<0.0001 in ExAC) truncating MYBPC3 variants identified in a cohort of 6179 HCM patients (3267 patients from OMGL, 2912 patients from LMM). When this rare variant frequency of 0.09160 is compared with a background population rate of 0.00086, there is a statistically significant case excess of 0.09074 (p<0.0001), which suggests that approximately 560 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 (6179)OMGL classLMM class ExAC frequency
1. c.25+1G>A essential splice site 2Pathogenic (2)0.000000
2. c.26-2A>G essential splice site 4Pathogenic (4)0.000051
3. c.100_110dup p.Val38Serfs*5frameshift 1Pathogenic (1)0.000000
4. c.121dup p.Arg41Profs*8frameshift 1Pathogenic (1)0.000000
5. c.126G>A p.W42Xnonsense 2Pathogenic (2)0.000000
6. c.177_187del p.Glu60AlafsX49frameshift 3Pathogenic (2)Pathogenic (1)0.000000
7. c.177dup p.Glu60Argfs*53frameshift 1Pathogenic (1)0.000000
8. c.211_212delinsTA p.Val71*frameshift 1Pathogenic (1)0.000000
9. c.255del p.Ser86Profs*10frameshift 1Pathogenic (1)0.000000
10. c.333_334insT p.E112Xnonsense 1Pathogenic (1)0.000000
11. c.351_352del p.Gly118Argfs*8frameshift 1Pathogenic (1)0.000000
12. c.391dup p.Ala131Glyfs*22frameshift 1Pathogenic (1)0.000000
13. c.431_432delGT p.Gly144AlafsX8frameshift 1Pathogenic (1)0.000000
14. c.436_437insA p.Thr146AsnfsX7frameshift 2Pathogenic (2)0.000000
15. c.443dup p.Ala149Serfs*4frameshift 2Pathogenic (2)0.000000
16. c.459delC frameshift 2Pathogenic (1)Pathogenic (1)0.000000
17. c.484C>T p.Q162Xnonsense 4Pathogenic (4)0.000000
18. c.506-1G>T essential splice site 1Pathogenic (1)0.000000
19. c.506-1G>A essential splice site 1Pathogenic (1)0.000000
20. c.533delT p.Val178GlyfsX7frameshift 1Pathogenic (1)0.000000
21. c.551_552insT p.Lys185GlufsX56frameshift 1Pathogenic (1)0.000000
22. c.553_562del p.Lys185Trpfs*12frameshift 1Pathogenic (1)0.000000
23. c.611_618delinsT p.Gly204Valfs*94frameshift 1Pathogenic (1)0.000000
24. c.613C>T p.Q205Xnonsense 1Pathogenic (1)0.000000
25. c.655-2del essential splice site 1Pathogenic (1)0.000000
26. c.655-1G>A essential splice site 1Pathogenic (1)0.000000
27. c.711C>A p.Y237Xnonsense 1Pathogenic (1)0.000000
28. c.731del p.Lys244Argfs*56frameshift 1Pathogenic (1)0.000000
29. c.743_746delACTG frameshift 1Pathogenic (1)0.000000
30. c.747C>A p.C249Xnonsense 2Pathogenic (2)0.000000
31. c.772+1G>A essential splice site 3Pathogenic (1)Pathogenic (2)0.000000
32. c.811_817delTTCCGCC frameshift 1Pathogenic (1)0.000000
33. c.821+1G>C essential splice site 1Pathogenic (1)0.000000
34. c.821+1G>A essential splice site 5Pathogenic (1)Pathogenic (4)0.000043
35. c.821+2T>C essential splice site 5Pathogenic (4)Pathogenic (1)0.000000
36. c.821+2T>G essential splice site 1Pathogenic (1)0.000000
37. c.833delG p.Gly278GlufsX22frameshift 3Pathogenic (2)Pathogenic (1)0.000000
38. c.913_914delTT frameshift 5Pathogenic (5)0.000000
39. c.927-2A>G essential splice site 10Pathogenic (8)Pathogenic (2)0.000000
40. c.932C>A p.S311Xnonsense 2Pathogenic (1)Pathogenic (1)0.000000
41. c.966G>A p.W322Xnonsense 1Pathogenic (1)0.000000
42. c.982delG frameshift 1Pathogenic (1)0.000000
43. c.993_994insT p.E332Xnonsense 1Pathogenic (1)0.000000
44. c.999C>G p.Y333Xnonsense 2Pathogenic (2)0.000000
45. c.1000G>T p.E334Xnonsense 1Pathogenic (1)0.000000
46. c.1021_1028del p.Gly341*frameshift 1Pathogenic (1)0.000000
47. c.1038_1042dupCGGCA frameshift 2Pathogenic (1)Pathogenic (1)0.000008
48. c.1090+1G>A essential splice site 2Pathogenic (1)Pathogenic (1)0.000000
49. c.1090+1G>T essential splice site 2Pathogenic (1)Pathogenic (1)0.000000
50. c.1090+2T>C essential splice site 1Pathogenic (1)0.000000
51. c.1120C>T p.Q374Xnonsense 1Pathogenic (1)0.000000
52. c.1156G>T p.E386Xnonsense 1Pathogenic (1)0.000000
53. c.1168delC frameshift 1Pathogenic (1)0.000000
54. c.1201C>T p.Q401Xnonsense 1Pathogenic (1)0.000000
55. c.1210C>T p.Q404Xnonsense 2Pathogenic (2)0.000000
56. c.1223+2T>C essential splice site 1Pathogenic (1)0.000000
57. c.1224-2A>G essential splice site 1Pathogenic (1)0.000000
58. c.1224-1G>T essential splice site 1Pathogenic (1)0.000000
59. c.1266_1267insTGAT p.Ile423*frameshift 1Pathogenic (1)0.000000
60. c.1273C>T p.Q425Xnonsense 2Pathogenic (1)Pathogenic (1)0.000000
61. c.1303C>T p.Q435Xnonsense 1Pathogenic (1)0.000000
62. c.1351+1G>A essential splice site 2Pathogenic (1)Pathogenic (1)0.000000
63. c.1351+2T>C essential splice site 1Pathogenic (1)0.000000
64. c.1352_1353del p.Glu451Alafs*23frameshift 1Pathogenic (1)0.000000
65. c.1357_1358delCC frameshift 2Pathogenic (2)0.000000
66. c.1359del p.Val454Cysfs*12frameshift 1Pathogenic (1)0.000000
67. c.1376_1377del p.Pro459Leufs*15frameshift 1Pathogenic (1)0.000000
68. c.1377delC frameshift 1Pathogenic (1)0.000000
69. c.1404del p.Gln469Serfs*19frameshift 1Pathogenic (1)0.000000
70. c.1405C>T p.Q469Xnonsense 1Pathogenic (1)0.000000
71. c.1457G>A p.W486Xnonsense 1Pathogenic (1)0.000000
72. c.1458-1G>A essential splice site 1Pathogenic (1)0.000000
73. c.1458G>A p.W486Xnonsense 1Pathogenic (1)0.000000
74. c.1523_1525delinsT p.Gln508Leufs*22frameshift 1Pathogenic (1)0.000000
75. c.1569dup p.His524Alafs*7frameshift 1Pathogenic (1)0.000000
76. c.1575T>G p.Y525Xnonsense 1Pathogenic (1)0.000000
77. c.1624+1G>A essential splice site 1Pathogenic (1)0.000000
78. c.1624+2T>C essential splice site 1Pathogenic (1)0.000000
79. c.1628delA frameshift 1Pathogenic (1)0.000000
80. c.1678delG p.Asp560ThrfsX19frameshift 1Pathogenic (1)0.000000
81. c.1693A>T p.K565Xnonsense 1Pathogenic (1)0.000000
82. c.1699_1700delGA p.Glu567GlyfsX4frameshift 1Pathogenic (1)0.000000
83. c.1797del p.His599Glnfs*3frameshift 1Pathogenic (1)0.000000
84. c.1800delA frameshift 1Pathogenic (1)0.000000
85. c.1863delC p.Phe621LeufsX42frameshift 2Pathogenic (2)0.000000
86. c.1869C>A p.C623Xnonsense 2Pathogenic (2)0.000000
87. c.1892delT frameshift 1Pathogenic (1)0.000000
88. c.1895delT p.Met632ArgfsX31frameshift 2Pathogenic (2)0.000000
89. c.1897+1G>A essential splice site 2Pathogenic (2)0.000000
90. c.1898-1G>A essential splice site 1Pathogenic (1)0.000000
91. c.1924C>T p.Q642Xnonsense 1Pathogenic (1)0.000000
92. c.1928-2A>G essential splice site 30Pathogenic (10)Pathogenic (20)0.000000
93. c.1999_2000delinsG p.Leu667AspfsX15frameshift 2Pathogenic (1)Pathogenic (1)0.000000
94. c.2013_2016delinsGG p.Pro672AspfsX20frameshift 1Pathogenic (1)0.000000
95. c.2040_2041insT p.Val681CysfsX12frameshift 1Pathogenic (1)0.000000
96. c.2048G>A p.W683Xnonsense 1Pathogenic (1)0.000000
97. c.2054_2067+11del p.Lys685Argfs*3frameshift 1Pathogenic (1)0.000000
98. c.2065C>T p.Q689Xnonsense 1Pathogenic (1)0.000000
99. c.2096delC frameshift 19Pathogenic (15)Pathogenic (4)0.000000
100. c.2113_2114insA p.Thr705AsnfsX3frameshift 1Pathogenic (1)0.000000
101. c.2149-1G>A essential splice site 1Pathogenic (1)0.000000
102. c.2149_2737del p.Leu717Alafs*11frameshift 1Pathogenic (1)0.000000
103. c.2161_2168del p.Thr721Profs*23frameshift 1Pathogenic (1)0.000000
104. c.2163delC p.Glu722ArgfsX32frameshift 1Pathogenic (1)0.000000
105. c.2182G>T p.E728Xnonsense 4Pathogenic (4)0.000000
106. c.2188del p.Thr730Profs*24frameshift 1Pathogenic (1)0.000000
107. c.2247C>A p.Y749Xnonsense 1Pathogenic (1)0.000000
108. c.2267delC frameshift 5Pathogenic (5)0.000000
109. c.2304_2308+2delCATCGGT essential splice site 1Pathogenic (1)0.000000
110. c.2308+1G>T essential splice site 1Pathogenic (1)0.000000
111. c.2308+1G>A essential splice site 3Pathogenic (2)Pathogenic (1)0.000000
112. c.2309-2A>G essential splice site 9Pathogenic (9)0.000000
113. c.2309-1G>A essential splice site 3Pathogenic (3)0.000000
114. c.2311_2312insG p.Val771GlyfsX62frameshift 3Pathogenic (3)0.000000
115. c.2371C>T p.Q791Xnonsense 1Pathogenic (1)0.000000
116. c.2373_2374insG p.Trp792ValfsTer41frameshift 66Pathogenic (40)Pathogenic (26)0.000037
117. c.2394_2395insT p.Gly799TrpfsX34frameshift 1Pathogenic (1)0.000000
118. c.2429_2503delins23 p.Arg810Profs*10frameshift 1Pathogenic (1)0.000000
119. c.2437A>T p.K813Xnonsense 1Pathogenic (1)0.000000
120. c.2454G>A p.W818Xnonsense 4Pathogenic (4)0.000000
121. c.2490_2491insT p.His831SerfsTer2frameshift 8Pathogenic (7)Pathogenic (1)0.000024
122. c.2502del p.Arg835Alafs*2frameshift 1Pathogenic (1)0.000000
123. c.2512dup p.Glu838Glyfs*46frameshift 1Pathogenic (1)0.000000
124. c.2517_2538del p.Val840ThrfsX32frameshift 1Pathogenic (1)0.000000
125. c.2524dup p.Tyr842Leufs*42frameshift 2Pathogenic (2)0.000000
126. c.2524_2525insT p.Tyr842LeufsX42frameshift 1Pathogenic (1)0.000000
127. c.2526C>G p.Y842Xnonsense 2Pathogenic (2)0.000000
128. c.2534_2538delGCGTC frameshift 2Pathogenic (1)Pathogenic (1)0.000000
129. c.2541C>A p.Y847Xnonsense 1Pathogenic (1)0.000000
130. c.2545del p.Val849Serfs*30frameshift 3Pathogenic (3)0.000000
131. c.2556_2557delinsTCT p.Gly853fsframeshift 5Pathogenic (4)Pathogenic (1)0.000000
132. c.2558delG frameshift 3Pathogenic (1)Pathogenic (2)0.000000
133. c.2584C>T p.Q862Xnonsense 1Pathogenic (1)0.000000
134. c.2603-2_2603-1delinsGA essential splice site 1Pathogenic (1)0.000000
135. c.2603-1G>C essential splice site 1Pathogenic (1)0.000000
136. c.2604_2605delinsA p.S871fsframeshift 10Pathogenic (8)Pathogenic (2)0.000000
137. c.2610_2611insC p.Ser871GlnfsX13frameshift 1Pathogenic (1)0.000000
138. c.2610delC frameshift 5Pathogenic (5)0.000000
139. c.2670G>A p.W890Xnonsense 7Pathogenic (7)0.000000
140. c.2690_2696del p.Gly897Glufs*25frameshift 1Pathogenic (1)0.000000
141. c.2718_2719dup p.Glu907Glyfs*18frameshift 1Pathogenic (1)0.000000
142. c.2737+1G>C essential splice site 1Pathogenic (1)0.000000
143. c.2737+2T>A essential splice site 1Pathogenic (1)0.000000
144. c.2738-2A>G essential splice site 1Pathogenic (1)0.000000
145. c.2747G>A p.W916Xnonsense 1Pathogenic (1)0.000000
146. c.2748G>A p.W916Xnonsense 1Pathogenic (1)0.000000
147. c.2780_2781delCA frameshift 1Pathogenic (1)0.000000
148. c.2789del p.Leu930Argfs*2frameshift 1Pathogenic (1)0.000000
149. c.2807dup p.Ala938Glyfs*113frameshift 1Pathogenic (1)0.000000
150. c.2827C>T p.R943Xnonsense 18Pathogenic (11)Pathogenic (7)0.000017
151. c.2833_2834delCG frameshift 1Pathogenic (1)0.000000
152. c.2864_2865delCT frameshift 14Pathogenic (8)Pathogenic (6)0.000000
153. c.2875_2876delAC p.Thr959GlyfsX91frameshift 1Pathogenic (1)0.000000
154. c.2905C>T p.Q969Xnonsense 5Pathogenic (2)Pathogenic (3)0.000000
155. c.2905+1G>C essential splice site 1Pathogenic (1)0.000000
156. c.2905+1G>A essential splice site 7Pathogenic (3)Pathogenic (4)0.000000
157. c.2905+2dup essential splice site 2Likely Pathogenic (2)0.000000
158. c.2906-2A>G essential splice site 1Pathogenic (1)0.000000
159. c.2920C>T p.Q974Xnonsense 3Pathogenic (3)0.000000
160. c.2943_2947delGACCA frameshift 2Pathogenic (2)0.000000
161. c.2953A>T p.K985Xnonsense 2Pathogenic (1)Pathogenic (1)0.000000
162. c.2965G>T p.E989Xnonsense 1Pathogenic (1)0.000000
163. c.2995-1G>A essential splice site 1Pathogenic (1)0.000000
164. c.3040delC p.Leu1014TrpfsX6frameshift 1Pathogenic (1)0.000000
165. c.3043dup p.Ala1015Glyfs*36frameshift 1Pathogenic (1)0.000000
166. c.3068_3069insA p.Asn1023LysfsX28frameshift 1Pathogenic (1)0.000000
167. c.3129C>A p.Y1043Xnonsense 3Pathogenic (3)0.000000
168. c.3163A>T p.K1055Xnonsense 4Pathogenic (4)0.000000
169. c.3166_3167insG p.Ala1056GlyfsX9frameshift 1Pathogenic (1)0.000000
170. c.3181C>T p.Q1061Xnonsense 4Pathogenic (3)Pathogenic (1)0.000016
171. c.3190+1G>A essential splice site 3Pathogenic (3)0.000000
172. c.3190+2T>G essential splice site 9Pathogenic (7)Pathogenic (2)0.000016
173. c.3192_3193insC p.Lys1065GlnfsX12frameshift 2Pathogenic (2)0.000000
174. c.3226_3227insT frameshift 18Pathogenic (12)Pathogenic (6)0.000000
175. c.3233G>A p.W1078Xnonsense 3Pathogenic (3)0.000022
176. c.3253G>T p.E1085Xnonsense 2Pathogenic (1)Pathogenic (1)0.000000
177. c.3257G>A p.W1086Xnonsense 1Pathogenic (1)0.000021
178. c.3271del p.Asp1091Metfs*98frameshift 2Pathogenic (2)0.000000
179. c.3286G>T p.E1096Xnonsense 4Pathogenic (3)Pathogenic (1)0.000000
180. c.3288delG frameshift 1Pathogenic (1)0.000000
181. c.3297dup p.Tyr1100Valfs*49frameshift 1Pathogenic (1)0.000000
182. c.3316del p.Asp1106Thrfs*83frameshift 1Pathogenic (1)0.000000
183. c.3330+1G>C essential splice site 1Pathogenic (1)0.000000
184. c.3330+2T>G essential splice site 11Pathogenic (11)0.000000
185. c.3331-1G>A essential splice site 1Pathogenic (1)0.000000
186. c.3332_3335dupAGTG p.W1112Xnonsense 1Pathogenic (1)0.000000
187. c.3335G>A p.W1112Xnonsense 1Pathogenic (1)0.000000
188. c.3357C>A p.Y1119Xnonsense 1Pathogenic (1)0.000000
189. c.3408C>A p.Y1136Xnonsense 4Pathogenic (3)Pathogenic (1)0.000000
190. c.3476_3477delTT frameshift 1Pathogenic (1)0.000000
191. c.3476_3479dupTTAT p.Pro1161TyrfsX9frameshift 1Pathogenic (1)0.000000
192. c.3490+1G>A essential splice site 1Pathogenic (1)0.000000
193. c.3491-2A>T essential splice site 3Pathogenic (3)0.000000
194. c.3600_3609delCTGCTGTGCT frameshift 3Pathogenic (3)Pathogenic (0)0.000000
195. c.3605delG frameshift 1Pathogenic (1)0.000000
196. c.3617delG frameshift 1Pathogenic (1)0.000000
197. c.3624delC frameshift 3Pathogenic (1)Pathogenic (2)0.000000
198. c.3624_3625insC p.Lys1209GlnfsX33frameshift 2Pathogenic (2)0.000000
199. c.3627+1G>A essential splice site 8Pathogenic (6)Pathogenic (2)0.000000
200. c.3627+1G>T essential splice site 2Pathogenic (2)0.000000
201. c.3690_3691delCA p.Phe1230LeufsX11frameshift 1Pathogenic (1)0.000000
202. c.3694A>T p.K1232Xnonsense 1Pathogenic (1)0.000000
203. c.3697C>T p.Q1233Xnonsense 13Likely Pathogenic (4)Pathogenic (9)0.000008
204. c.3735delC frameshift 1Likely Pathogenic (1)0.000000
205. c.3753T>G p.Y1251Xnonsense 1Pathogenic (1)0.000000
206. c.3776delA frameshift 1Pathogenic (1)0.000000
207. c.3792_3793del p.Cys1264*frameshift 1Likely Pathogenic (1)0.000000
208. c.3811C>T p.R1271Xnonsense 2VUS (1)Pathogenic (1)0.000025
209. c.3815-1G>A essential splice site 1Pathogenic (1)0.000000
210. c.3825A>G p.X1275TrpextX77nonsense 1Likely Pathogenic (1)0.000000
211. c.*26+2T>C essential splice site 1Likely Pathogenic (1)0.000000

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.