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