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