MYBPC3 non-truncating variants in HCM cohorts

MYBPC3 gene summary
Overview of MYBPC3 in HCM

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