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.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.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.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.3798C>G p.C1266Wmissense 4VUS (4)0.000000
23. c.1591G>A p.G531Rmissense 4Likely Pathogenic (1)VUS favour pathogenic (3)0.000017
24. c.3277G>T p.G1093Cmissense 4VUS (3)VUS (1)0.000020
25. c.3742_3759dup p.Gly1248_Cys1253dupinframe 4Likely Pathogenic (4)0.000000
26. c.2210C>T p.T737Mmissense 4VUS (3)VUS (1)0.000050
27. c.1483C>T p.R495Wmissense 4Likely Pathogenic (2)VUS favour pathogenic (2)0.000000
28. c.532G>A p.V178Mmissense 3VUS (1)VUS favour pathogenic (2)0.000020
29. c.355G>A p.E119Kmissense 3VUS (3)0.000000
30. c.1828G>C p.D610Hmissense 3VUS (1)VUS favour benign (2)0.000058
31. c.1720C>T p.R574Wmissense 3VUS (3)0.000054
32. c.1790G>A p.R597Qmissense 3VUS (1)VUS favour pathogenic (2)0.000000
33. c.3767_3769delCCA p.Thr1256delinframe 3Likely Pathogenic (3)0.000000
34. c.2450G>A p.R817Qmissense 3VUS favour pathogenic (3)0.000016
35. c.1037G>A p.R346Hmissense 3VUS (1)VUS (2)0.000000
36. c.1123G>A p.V375Mmissense 3VUS (3)0.000009
37. c.1213A>G p.M405Vmissense 2VUS (1)Pathogenic (1)0.000000
38. c.1934C>T p.P645Lmissense 2VUS (2)0.000000
39. c.3676C>T p.R1226Cmissense 2VUS (1)VUS (1)0.000058
40. c.3005G>A p.R1002Qmissense 2VUS (2)0.000046
41. c.3751T>C p.Y1251Hmissense 2VUS (2)0.000000
42. c.636C>G p.S212Rmissense 2VUS favour pathogenic (2)0.000000
43. c.1886T>C p.L629Pmissense 2VUS (2)0.000000
44. c.2449C>T p.R817Wmissense 2VUS (1)VUS (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.3373G>A p.V1125Mmissense 2VUS (1)VUS favour pathogenic (1)0.000022
48. c.3470C>T p.P1157Lmissense 2VUS (2)0.000093
49. c.373G>T p.A125Smissense 2VUS (1)VUS (1)0.000000
50. c.2432A>G p.K811Rmissense 2VUS (2)0.000000
51. c.2882C>T p.P961Lmissense 2VUS (2)0.000048
52. c.3582_3593delGGGCTACACTGC inframe 2Likely Pathogenic (1)0.000000
53. c.2197C>T p.R733Cmissense 2Likely Pathogenic (1)VUS (1)0.000085
54. c.2269G>A p.V757Mmissense 2VUS (1)VUS (1)0.000066
55. c.557C>T p.P186Lmissense 2VUS (2)0.000047
56. c.3752A>G p.Y1251Cmissense 2VUS (2)0.000000
57. c.3455_3466del p.Ala1152_Lys1155delinframe 2Likely Pathogenic (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.2320G>A p.A774Tmissense 2VUS (2)0.000000
61. c.844C>T p.R282Wmissense 2Likely Pathogenic (1)VUS favour pathogenic (1)0.000000
62. c.2300A>G p.K767Rmissense 2VUS (2)0.000016
63. c.1841A>G p.Y614Cmissense 2VUS (1)VUS favour pathogenic (1)0.000000
64. c.818G>A p.R273Hmissense 2VUS (2)0.000042
65. c.2219G>C p.G740Amissense 2VUS (2)0.000000
66. c.1456T>G p.W486Gmissense 2VUS (1)Likely Pathogenic (1)0.000000
67. c.2436G>T p.K812Nmissense 1VUS (1)0.000000
68. c.2234A>G p.D745Gmissense 1VUS (1)0.000000
69. c.2528_2536delAGATGCGCG p.Glu843_Arg845delinframe 1Pathogenic (1)0.000000
70. c.3580G>A p.A1194Tmissense 1VUS (1)0.000008
71. c.3572C>T p.S1191Lmissense 1VUS (1)0.000016
72. c.1540A>G p.I514Vmissense 1VUS (1)0.000008
73. c.1358C>T p.P453Lmissense 1VUS (1)0.000008
74. c.2503C>T p.R835Cmissense 1VUS (1)0.000024
75. c.3049G>A p.E1017Kmissense 1VUS favour benign (1)0.000085
76. c.1291G>A p.D431Nmissense 1VUS (1)0.000028
77. c.2938C>T p.R980Cmissense 1VUS (1)0.000062
78. c.2170C>T p.R724Wmissense 1VUS (1)0.000019
79. c.1471G>A p.V491Mmissense 1VUS (1)0.000058
80. c.2557G>A p.G853Smissense 1VUS (1)0.000008
81. c.188G>A p.R63Qmissense 1VUS (1)0.000039
82. c.1535T>A p.L512Qmissense 1VUS favour pathogenic (1)0.000000
83. c.1021G>C p.G341Rmissense 1VUS (1)0.000000
84. c.1294G>A p.A432Tmissense 1VUS (1)0.000037
85. c.241G>T p.V81Fmissense 1VUS (1)0.000000
86. c.3364A>T p.T1122Smissense 1Likely Pathogenic (1)0.000000
87. c.1231A>G p.I411Vmissense 1VUS (1)0.000000
88. c.3065G>A p.R1022Hmissense 1VUS favour pathogenic (1)0.000000
89. c.2708G>A p.G903Dmissense 1Likely Pathogenic (1)0.000000
90. c.365C>A p.A122Dmissense 1VUS (1)0.000000
91. c.3548T>G p.F1183Cmissense 1Likely Pathogenic (1)0.000000
92. c.2641G>A p.V881Imissense 1VUS (1)0.000018
93. c.2671C>T p.R891Wmissense 1Likely Pathogenic (1)0.000031
94. c.1188G>T p.W396Cmissense 1VUS (1)0.000000
95. c.436A>C p.T146Pmissense 1VUS (1)0.000000
96. c.326C>T p.A109Vmissense 1VUS (1)0.000000
97. c.3742G>A p.G1248Rmissense 1VUS (1)0.000033
98. c.931T>A p.S311Tmissense 1VUS (1)0.000000
99. c.2654C>T p.T885Mmissense 1VUS (1)0.000022
100. c.3316G>A p.D1106Nmissense 1VUS (1)0.000061
101. c.2198G>A p.R733Hmissense 1VUS (1)0.000034
102. c.3656T>C p.L1219Pmissense 1VUS (1)0.000000
103. c.103C>T p.R35Wmissense 1VUS (1)0.000056
104. c.631G>A p.D211Nmissense 1VUS (1)0.000009
105. c.2265C>A p.N755Kmissense 1Pathogenic (1)0.000000
106. c.3G>C p.Met1?missense 1Likely Pathogenic (1)0.000000
107. c.1112C>T p.P371Lmissense 1VUS (1)0.000028
108. c.3791G>A p.C1264Ymissense 1VUS (1)0.000008
109. c.1731G>C p.W577Cmissense 1VUS (1)0.000000
110. c.148A>G p.S50Gmissense 1VUS (1)0.000038
111. c.2533C>T p.R845Cmissense 1VUS favour pathogenic (1)0.000000
112. c.2953A>G p.K985Emissense 1Pathogenic (1)0.000000
113. c.799C>G p.L267Vmissense 1VUS (1)0.000080
114. c.3614G>C p.R1205Pmissense 1Likely Pathogenic (1)0.000000
115. c.1080G>C p.K360Nmissense 1VUS (1)0.000000
116. c.223G>A p.D75Nmissense 1VUS favour pathogenic (1)0.000091
117. c.2993A>G p.Q998Rmissense 1VUS favour pathogenic (1)0.000000
118. c.481C>A p.P161Tmissense 1VUS favour pathogenic (1)0.000041
119. c.2939G>A p.R980Hmissense 1VUS (1)0.000000
120. c.2312T>C p.V771Amissense 1VUS (1)0.000000
121. c.3713T>C p.L1238Pmissense 1Likely Pathogenic (1)0.000000
122. c.2909G>A p.R970Qmissense 1Likely Pathogenic (1)0.000032
123. c.518C>A p.T173Nmissense 1VUS (1)0.000000
124. c.2518G>A p.V840Mmissense 1VUS (1)0.000016
125. c.1950C>G p.D650Emissense 1VUS (1)0.000000
126. c.1672G>A p.A558Tmissense 1VUS (1)0.000008
127. c.3415G>A p.V1139Imissense 1VUS (1)0.000087
128. c.1789C>T p.R597Wmissense 1VUS (1)0.000038
129. c.3083C>G p.T1028Smissense 1VUS (1)0.000000
130. c.1153G>A p.V385Mmissense 1VUS (1)0.000010
131. c.3206C>A p.P1069Hmissense 1Likely Pathogenic (1)0.000000
132. c.994G>A p.E332Kmissense 1VUS (1)0.000009
133. c.3739G>A p.D1247Nmissense 1VUS (1)0.000000
134. c.1433C>T p.S478Lmissense 1Likely Pathogenic (1)0.000017
135. c.2723A>G p.Y908Cmissense 1VUS (1)0.000062
136. c.187C>T p.R63Wmissense 1VUS (1)0.000077
137. c.1586C>G p.T529Smissense 1VUS favour pathogenic (1)0.000000
138. c.2381C>A p.P794Qmissense 1VUS (1)0.000000
139. c.1A>T p.Met1?missense 1Likely Pathogenic (1)0.000000
140. c.3334_3351del p.Trp1112_Glu1117delinframe 1Likely Pathogenic (1)0.000000
141. c.1174G>T p.A392Smissense 1VUS (1)0.000000
142. c.1591G>C p.G531Rmissense 1VUS favour pathogenic (1)0.000017
143. c.256_258del p.Ser86delinframe 1VUS (1)0.000000
144. c.3797G>A p.C1266Ymissense 1Likely Pathogenic (1)0.000000
145. c.3281A>T p.N1094Imissense 1VUS (1)0.000000
146. c.932C>T p.S311Lmissense 1VUS (1)0.000000
147. c.1418T>C p.F473Smissense 1VUS (1)0.000000
148. c.1397T>A p.M466Kmissense 1VUS (1)0.000008
149. c.853G>A p.D285Nmissense 1VUS (1)0.000000
150. c.1960C>T p.R654Cmissense 1VUS favour benign (1)0.000008
151. c.2504G>T p.R835Lmissense 1Likely Pathogenic (1)0.000074
152. c.2828G>A p.R943Qmissense 1VUS (1)0.000025
153. c.3019T>C p.W1007Rmissense 1VUS (1)0.000000
154. c.2030C>T p.P677Lmissense 1VUS (1)0.000000
155. c.3614G>A p.R1205Qmissense 1VUS (1)0.000016
156. c.451G>A p.D151Nmissense 1VUS (1)0.000041
157. c.2249C>T p.T750Mmissense 1Likely Pathogenic (1)0.000024
158. c.1505G>T p.R502Lmissense 1VUS favour pathogenic (1)0.000000
159. c.1072G>A p.D358Nmissense 1VUS (1)0.000008
160. c.104G>A p.R35Qmissense 1VUS (1)0.000079
161. c.1685C>T p.A562Vmissense 1VUS (1)0.000008
162. c.1455A>T p.K485Nmissense 1VUS (1)0.000000
163. c.49C>T p.R17Wmissense 1VUS (1)0.000023
164. c.290C>T p.A97Vmissense 1VUS favour pathogenic (1)0.000000
165. c.2834G>A p.R945Qmissense 1VUS (1)0.000000
166. c.701C>A p.T234Nmissense 1Likely Pathogenic (1)0.000000
167. c.1756C>G p.P586Amissense 1Likely Pathogenic (1)0.000000
168. c.1343T>C p.F448Smissense 1Likely Pathogenic (1)0.000000
169. c.3413G>C p.R1138Pmissense 1VUS (1)0.000000
170. c.2525A>G p.Y842Cmissense 1VUS (1)0.000000
171. c.1778C>T p.S593Fmissense 1VUS favour pathogenic (1)0.000034
172. c.3452C>T p.A1151Vmissense 1VUS (1)0.000078
173. c.713G>A p.R238Hmissense 1VUS (1)0.000074
174. c.566T>A p.V189Dmissense 1VUS (1)0.000000
175. c.2560A>G p.M854Vmissense 1VUS (1)0.000000
176. c.3746G>T p.G1249Vmissense 1VUS (1)0.000000
177. c.3605G>A p.C1202Ymissense 1Likely Pathogenic (1)0.000000
178. c.3098G>A p.R1033Qmissense 1VUS (1)0.000000
179. c.2968C>G p.P990Amissense 1Likely Pathogenic (1)0.000000
180. c.3728C>G p.P1243Rmissense 1VUS (1)0.000000
181. c.146_148delTCA p.Ile49delinframe 1VUS (1)0.000039
182. c.1097A>C p.Q366Pmissense 1VUS (1)0.000000
183. c.3256T>C p.W1086Rmissense 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.