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