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