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

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.