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

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.