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