MYBPC3 non-truncating variants in HCM cohorts


The table below lists the 610 rare (MAF<0.0001 in ExAC) non-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 0.09872 is compared with a background population rate of 0.01884, there is a statistically significant case excess of 0.07988 (p<0.0001), which suggests that approximately 494 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.1504C>T p.R502Wmissense 104Pathogenic (59)Pathogenic (45)0.000024
2. c.772G>A p.E258Kmissense 68Pathogenic (47)Pathogenic (21)0.000039
3. c.1624G>C p.E542Qmissense 41Pathogenic (24)Likely Pathogenic (17)0.000024
4. c.655G>C p.V219Lmissense 26Likely Pathogenic (18)Likely Pathogenic (8)0.000000
5. c.2429G>A p.R810Hmissense 19VUS (11)VUS favour pathogenic (8)0.000033
6. c.1483C>G p.R495Gmissense 14Likely Pathogenic (10)Likely Pathogenic (4)0.000000
7. c.1484G>A p.R495Qmissense 14Likely Pathogenic (4)VUS favour pathogenic (10)0.000008
8. c.442G>A p.G148Rmissense 11Likely Pathogenic (4)VUS favour pathogenic (7)0.000042
9. c.2308G>A p.D770Nmissense 11Likely Pathogenic (5)Likely Pathogenic (6)0.000008
10. c.3613C>T p.R1205Wmissense 10Likely Pathogenic (10)0.000016
11. c.3771C>A p.N1257Kmissense 9Likely Pathogenic (9)0.000000
12. c.1505G>A p.R502Qmissense 8Pathogenic (2)Pathogenic (6)0.000000
13. c.2573G>A p.S858Nmissense 6Likely Pathogenic (2)VUS favour pathogenic (4)0.000000
14. c.2459G>A p.R820Qmissense 6VUS (5)Likely Pathogenic (1)0.000016
15. c.3065G>C p.R1022Pmissense 6Likely Pathogenic (5)VUS favour pathogenic (1)0.000025
16. c.710A>C p.Y237Smissense 6Likely Pathogenic (3)Likely Pathogenic (3)0.000000
17. c.2374T>C p.W792Rmissense 5Likely Pathogenic (5)0.000000
18. c.3064C>T p.R1022Cmissense 5VUS (1)VUS favour pathogenic (4)0.000008
19. c.1828G>A p.D610Nmissense 5VUS (2)VUS (3)0.000000
20. c.1483C>T p.R495Wmissense 4Likely Pathogenic (2)VUS favour pathogenic (2)0.000000
21. c.3763G>A p.A1255Tmissense 4VUS (3)VUS favour pathogenic (1)0.000075
22. c.2873C>T p.T958Imissense 4VUS (1)VUS favour benign (3)0.000065
23. c.3798C>G p.C1266Wmissense 4VUS (4)0.000000
24. c.1591G>A p.G531Rmissense 4Likely Pathogenic (1)VUS favour pathogenic (3)0.000017
25. c.3277G>T p.G1093Cmissense 4VUS (3)VUS (1)0.000020
26. c.3742_3759dup p.Gly1248_Cys1253dupinframe 4Likely Pathogenic (4)0.000000
27. c.2210C>T p.T737Mmissense 4VUS (3)VUS (1)0.000050
28. c.3767_3769delCCA p.Thr1256delinframe 3Likely Pathogenic (3)0.000000
29. c.2450G>A p.R817Qmissense 3VUS favour pathogenic (3)0.000016
30. c.1037G>A p.R346Hmissense 3VUS (1)VUS (2)0.000000
31. c.1123G>A p.V375Mmissense 3VUS (3)0.000009
32. c.532G>A p.V178Mmissense 3VUS (1)VUS favour pathogenic (2)0.000020
33. c.355G>A p.E119Kmissense 3VUS (3)0.000000
34. c.1828G>C p.D610Hmissense 3VUS (1)VUS favour benign (2)0.000058
35. c.1720C>T p.R574Wmissense 3VUS (3)0.000054
36. c.1790G>A p.R597Qmissense 3VUS (1)VUS favour pathogenic (2)0.000000
37. c.2882C>T p.P961Lmissense 2VUS (2)0.000048
38. c.2197C>T p.R733Cmissense 2Likely Pathogenic (1)VUS (1)0.000085
39. c.2269G>A p.V757Mmissense 2VUS (1)VUS (1)0.000066
40. c.3582_3593delGGGCTACACTGC inframe 2Likely Pathogenic (1)0.000000
41. c.3752A>G p.Y1251Cmissense 2VUS (2)0.000000
42. c.557C>T p.P186Lmissense 2VUS (2)0.000047
43. c.3455_3466del p.Ala1152_Lys1155delinframe 2Likely Pathogenic (2)0.000000
44. c.1513_1515delAAG inframe 2VUS favour pathogenic (2)0.000000
45. c.814C>T p.R272Cmissense 2VUS (2)0.000083
46. c.2300A>G p.K767Rmissense 2VUS (2)0.000016
47. c.2320G>A p.A774Tmissense 2VUS (2)0.000000
48. c.844C>T p.R282Wmissense 2Likely Pathogenic (1)VUS favour pathogenic (1)0.000000
49. c.1841A>G p.Y614Cmissense 2VUS (1)VUS favour pathogenic (1)0.000000
50. c.818G>A p.R273Hmissense 2VUS (2)0.000042
51. c.2219G>C p.G740Amissense 2VUS (2)0.000000
52. c.1456T>G p.W486Gmissense 2VUS (1)Likely Pathogenic (1)0.000000
53. c.1213A>G p.M405Vmissense 2VUS (1)Pathogenic (1)0.000000
54. c.1934C>T p.P645Lmissense 2VUS (2)0.000000
55. c.3005G>A p.R1002Qmissense 2VUS (2)0.000046
56. c.3676C>T p.R1226Cmissense 2VUS (1)VUS (1)0.000058
57. c.3751T>C p.Y1251Hmissense 2VUS (2)0.000000
58. c.636C>G p.S212Rmissense 2VUS favour pathogenic (2)0.000000
59. c.1886T>C p.L629Pmissense 2VUS (2)0.000000
60. c.1766G>A p.R589Hmissense 2VUS (2)0.000000
61. c.1021G>A p.G341Smissense 2VUS (1)VUS favour pathogenic (1)0.000025
62. c.2449C>T p.R817Wmissense 2VUS (1)VUS (1)0.000000
63. c.3470C>T p.P1157Lmissense 2VUS (2)0.000093
64. c.3373G>A p.V1125Mmissense 2VUS (1)VUS favour pathogenic (1)0.000022
65. c.2432A>G p.K811Rmissense 2VUS (2)0.000000
66. c.373G>T p.A125Smissense 2VUS (1)VUS (1)0.000000
67. c.256_258del p.Ser86delinframe 1VUS (1)0.000000
68. c.1591G>C p.G531Rmissense 1VUS favour pathogenic (1)0.000017
69. c.3797G>A p.C1266Ymissense 1Likely Pathogenic (1)0.000000
70. c.853G>A p.D285Nmissense 1VUS (1)0.000000
71. c.1960C>T p.R654Cmissense 1VUS favour benign (1)0.000008
72. c.3281A>T p.N1094Imissense 1VUS (1)0.000000
73. c.932C>T p.S311Lmissense 1VUS (1)0.000000
74. c.1418T>C p.F473Smissense 1VUS (1)0.000000
75. c.1397T>A p.M466Kmissense 1VUS (1)0.000008
76. c.3019T>C p.W1007Rmissense 1VUS (1)0.000000
77. c.2030C>T p.P677Lmissense 1VUS (1)0.000000
78. c.3614G>A p.R1205Qmissense 1VUS (1)0.000016
79. c.2504G>T p.R835Lmissense 1Likely Pathogenic (1)0.000074
80. c.2828G>A p.R943Qmissense 1VUS (1)0.000025
81. c.1072G>A p.D358Nmissense 1VUS (1)0.000008
82. c.104G>A p.R35Qmissense 1VUS (1)0.000079
83. c.1685C>T p.A562Vmissense 1VUS (1)0.000008
84. c.451G>A p.D151Nmissense 1VUS (1)0.000041
85. c.2249C>T p.T750Mmissense 1Likely Pathogenic (1)0.000024
86. c.1505G>T p.R502Lmissense 1VUS favour pathogenic (1)0.000000
87. c.290C>T p.A97Vmissense 1VUS favour pathogenic (1)0.000000
88. c.2834G>A p.R945Qmissense 1VUS (1)0.000000
89. c.1455A>T p.K485Nmissense 1VUS (1)0.000000
90. c.49C>T p.R17Wmissense 1VUS (1)0.000023
91. c.701C>A p.T234Nmissense 1Likely Pathogenic (1)0.000000
92. c.1756C>G p.P586Amissense 1Likely Pathogenic (1)0.000000
93. c.1343T>C p.F448Smissense 1Likely Pathogenic (1)0.000000
94. c.2525A>G p.Y842Cmissense 1VUS (1)0.000000
95. c.1778C>T p.S593Fmissense 1VUS favour pathogenic (1)0.000034
96. c.3413G>C p.R1138Pmissense 1VUS (1)0.000000
97. c.713G>A p.R238Hmissense 1VUS (1)0.000074
98. c.566T>A p.V189Dmissense 1VUS (1)0.000000
99. c.2560A>G p.M854Vmissense 1VUS (1)0.000000
100. c.3452C>T p.A1151Vmissense 1VUS (1)0.000078
101. c.3746G>T p.G1249Vmissense 1VUS (1)0.000000
102. c.3605G>A p.C1202Ymissense 1Likely Pathogenic (1)0.000000
103. c.3098G>A p.R1033Qmissense 1VUS (1)0.000000
104. c.3728C>G p.P1243Rmissense 1VUS (1)0.000000
105. c.146_148delTCA p.Ile49delinframe 1VUS (1)0.000039
106. c.2968C>G p.P990Amissense 1Likely Pathogenic (1)0.000000
107. c.3256T>C p.W1086Rmissense 1VUS (1)0.000000
108. c.1097A>C p.Q366Pmissense 1VUS (1)0.000000
109. c.2528_2536delAGATGCGCG p.Glu843_Arg845delinframe 1Pathogenic (1)0.000000
110. c.3580G>A p.A1194Tmissense 1VUS (1)0.000008
111. c.2436G>T p.K812Nmissense 1VUS (1)0.000000
112. c.2234A>G p.D745Gmissense 1VUS (1)0.000000
113. c.3572C>T p.S1191Lmissense 1VUS (1)0.000016
114. c.1540A>G p.I514Vmissense 1VUS (1)0.000008
115. c.3049G>A p.E1017Kmissense 1VUS favour benign (1)0.000085
116. c.1291G>A p.D431Nmissense 1VUS (1)0.000028
117. c.2938C>T p.R980Cmissense 1VUS (1)0.000062
118. c.2170C>T p.R724Wmissense 1VUS (1)0.000019
119. c.1358C>T p.P453Lmissense 1VUS (1)0.000008
120. c.2503C>T p.R835Cmissense 1VUS (1)0.000024
121. c.1535T>A p.L512Qmissense 1VUS favour pathogenic (1)0.000000
122. c.1021G>C p.G341Rmissense 1VUS (1)0.000000
123. c.1294G>A p.A432Tmissense 1VUS (1)0.000037
124. c.1471G>A p.V491Mmissense 1VUS (1)0.000058
125. c.2557G>A p.G853Smissense 1VUS (1)0.000008
126. c.188G>A p.R63Qmissense 1VUS (1)0.000039
127. c.1231A>G p.I411Vmissense 1VUS (1)0.000000
128. c.3065G>A p.R1022Hmissense 1VUS favour pathogenic (1)0.000000
129. c.2708G>A p.G903Dmissense 1Likely Pathogenic (1)0.000000
130. c.241G>T p.V81Fmissense 1VUS (1)0.000000
131. c.3364A>T p.T1122Smissense 1Likely Pathogenic (1)0.000000
132. c.365C>A p.A122Dmissense 1VUS (1)0.000000
133. c.2671C>T p.R891Wmissense 1Likely Pathogenic (1)0.000031
134. c.3548T>G p.F1183Cmissense 1Likely Pathogenic (1)0.000000
135. c.2641G>A p.V881Imissense 1VUS (1)0.000018
136. c.436A>C p.T146Pmissense 1VUS (1)0.000000
137. c.326C>T p.A109Vmissense 1VUS (1)0.000000
138. c.3742G>A p.G1248Rmissense 1VUS (1)0.000033
139. c.1188G>T p.W396Cmissense 1VUS (1)0.000000
140. c.2198G>A p.R733Hmissense 1VUS (1)0.000034
141. c.3656T>C p.L1219Pmissense 1VUS (1)0.000000
142. c.103C>T p.R35Wmissense 1VUS (1)0.000056
143. c.931T>A p.S311Tmissense 1VUS (1)0.000000
144. c.2654C>T p.T885Mmissense 1VUS (1)0.000022
145. c.3316G>A p.D1106Nmissense 1VUS (1)0.000061
146. c.3791G>A p.C1264Ymissense 1VUS (1)0.000008
147. c.631G>A p.D211Nmissense 1VUS (1)0.000009
148. c.2265C>A p.N755Kmissense 1Pathogenic (1)0.000000
149. c.3G>C p.Met1?missense 1Likely Pathogenic (1)0.000000
150. c.1112C>T p.P371Lmissense 1VUS (1)0.000028
151. c.799C>G p.L267Vmissense 1VUS (1)0.000080
152. c.3614G>C p.R1205Pmissense 1Likely Pathogenic (1)0.000000
153. c.1731G>C p.W577Cmissense 1VUS (1)0.000000
154. c.148A>G p.S50Gmissense 1VUS (1)0.000038
155. c.2533C>T p.R845Cmissense 1VUS favour pathogenic (1)0.000000
156. c.2953A>G p.K985Emissense 1Pathogenic (1)0.000000
157. c.1080G>C p.K360Nmissense 1VUS (1)0.000000
158. c.223G>A p.D75Nmissense 1VUS favour pathogenic (1)0.000091
159. c.2993A>G p.Q998Rmissense 1VUS favour pathogenic (1)0.000000
160. c.2939G>A p.R980Hmissense 1VUS (1)0.000000
161. c.481C>A p.P161Tmissense 1VUS favour pathogenic (1)0.000041
162. c.518C>A p.T173Nmissense 1VUS (1)0.000000
163. c.2518G>A p.V840Mmissense 1VUS (1)0.000016
164. c.1950C>G p.D650Emissense 1VUS (1)0.000000
165. c.1672G>A p.A558Tmissense 1VUS (1)0.000008
166. c.2312T>C p.V771Amissense 1VUS (1)0.000000
167. c.3713T>C p.L1238Pmissense 1Likely Pathogenic (1)0.000000
168. c.2909G>A p.R970Qmissense 1Likely Pathogenic (1)0.000032
169. c.3083C>G p.T1028Smissense 1VUS (1)0.000000
170. c.1153G>A p.V385Mmissense 1VUS (1)0.000010
171. c.3415G>A p.V1139Imissense 1VUS (1)0.000087
172. c.1789C>T p.R597Wmissense 1VUS (1)0.000038
173. c.2723A>G p.Y908Cmissense 1VUS (1)0.000062
174. c.187C>T p.R63Wmissense 1VUS (1)0.000077
175. c.1586C>G p.T529Smissense 1VUS favour pathogenic (1)0.000000
176. c.3206C>A p.P1069Hmissense 1Likely Pathogenic (1)0.000000
177. c.994G>A p.E332Kmissense 1VUS (1)0.000009
178. c.3739G>A p.D1247Nmissense 1VUS (1)0.000000
179. c.1433C>T p.S478Lmissense 1Likely Pathogenic (1)0.000017
180. c.3334_3351del p.Trp1112_Glu1117delinframe 1Likely Pathogenic (1)0.000000
181. c.1174G>T p.A392Smissense 1VUS (1)0.000000
182. c.2381C>A p.P794Qmissense 1VUS (1)0.000000
183. c.1A>T p.Met1?missense 1Likely Pathogenic (1)0.000000

References

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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.