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