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