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