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