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