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.1591G>A p.G531Rmissense 4Likely Pathogenic (1)VUS favour pathogenic (3)0.000017
21. c.3277G>T p.G1093Cmissense 4VUS (3)VUS (1)0.000020
22. c.3742_3759dup p.Gly1248_Cys1253dupinframe 4Likely Pathogenic (4)0.000000
23. c.2210C>T p.T737Mmissense 4VUS (3)VUS (1)0.000050
24. c.1483C>T p.R495Wmissense 4Likely Pathogenic (2)VUS favour pathogenic (2)0.000000
25. c.3798C>G p.C1266Wmissense 4VUS (4)0.000000
26. c.3763G>A p.A1255Tmissense 4VUS (3)VUS favour pathogenic (1)0.000075
27. c.2873C>T p.T958Imissense 4VUS (1)VUS favour benign (3)0.000065
28. c.1037G>A p.R346Hmissense 3VUS (1)VUS (2)0.000000
29. c.1790G>A p.R597Qmissense 3VUS (1)VUS favour pathogenic (2)0.000000
30. c.1123G>A p.V375Mmissense 3VUS (3)0.000009
31. c.355G>A p.E119Kmissense 3VUS (3)0.000000
32. c.1720C>T p.R574Wmissense 3VUS (3)0.000054
33. c.2450G>A p.R817Qmissense 3VUS favour pathogenic (3)0.000016
34. c.532G>A p.V178Mmissense 3VUS (1)VUS favour pathogenic (2)0.000020
35. c.1828G>C p.D610Hmissense 3VUS (1)VUS favour benign (2)0.000058
36. c.3767_3769delCCA p.Thr1256delinframe 3Likely Pathogenic (3)0.000000
37. c.3582_3593delGGGCTACACTGC inframe 2Likely Pathogenic (1)0.000000
38. c.3752A>G p.Y1251Cmissense 2VUS (2)0.000000
39. c.557C>T p.P186Lmissense 2VUS (2)0.000047
40. c.636C>G p.S212Rmissense 2VUS favour pathogenic (2)0.000000
41. c.3455_3466del p.Ala1152_Lys1155delinframe 2Likely Pathogenic (2)0.000000
42. c.844C>T p.R282Wmissense 2Likely Pathogenic (1)VUS favour pathogenic (1)0.000000
43. c.2300A>G p.K767Rmissense 2VUS (2)0.000016
44. c.1766G>A p.R589Hmissense 2VUS (2)0.000000
45. c.1021G>A p.G341Smissense 2VUS (1)VUS favour pathogenic (1)0.000025
46. c.818G>A p.R273Hmissense 2VUS (2)0.000042
47. c.2219G>C p.G740Amissense 2VUS (2)0.000000
48. c.373G>T p.A125Smissense 2VUS (1)VUS (1)0.000000
49. c.1934C>T p.P645Lmissense 2VUS (2)0.000000
50. c.3005G>A p.R1002Qmissense 2VUS (2)0.000046
51. c.2882C>T p.P961Lmissense 2VUS (2)0.000048
52. c.3751T>C p.Y1251Hmissense 2VUS (2)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.1513_1515delAAG inframe 2VUS favour pathogenic (2)0.000000
56. c.814C>T p.R272Cmissense 2VUS (2)0.000083
57. c.1886T>C p.L629Pmissense 2VUS (2)0.000000
58. c.2320G>A p.A774Tmissense 2VUS (2)0.000000
59. c.1841A>G p.Y614Cmissense 2VUS (1)VUS favour pathogenic (1)0.000000
60. c.2449C>T p.R817Wmissense 2VUS (1)VUS (1)0.000000
61. c.3470C>T p.P1157Lmissense 2VUS (2)0.000093
62. c.3373G>A p.V1125Mmissense 2VUS (1)VUS favour pathogenic (1)0.000022
63. c.2432A>G p.K811Rmissense 2VUS (2)0.000000
64. c.1456T>G p.W486Gmissense 2VUS (1)Likely Pathogenic (1)0.000000
65. c.1213A>G p.M405Vmissense 2VUS (1)Pathogenic (1)0.000000
66. c.3676C>T p.R1226Cmissense 2VUS (1)VUS (1)0.000058
67. c.1418T>C p.F473Smissense 1VUS (1)0.000000
68. c.853G>A p.D285Nmissense 1VUS (1)0.000000
69. c.3065G>A p.R1022Hmissense 1VUS favour pathogenic (1)0.000000
70. c.3281A>T p.N1094Imissense 1VUS (1)0.000000
71. c.3019T>C p.W1007Rmissense 1VUS (1)0.000000
72. c.2030C>T p.P677Lmissense 1VUS (1)0.000000
73. c.3614G>A p.R1205Qmissense 1VUS (1)0.000016
74. c.2504G>T p.R835Lmissense 1Likely Pathogenic (1)0.000074
75. c.1072G>A p.D358Nmissense 1VUS (1)0.000008
76. c.2671C>T p.R891Wmissense 1Likely Pathogenic (1)0.000031
77. c.1685C>T p.A562Vmissense 1VUS (1)0.000008
78. c.2641G>A p.V881Imissense 1VUS (1)0.000018
79. c.2249C>T p.T750Mmissense 1Likely Pathogenic (1)0.000024
80. c.2834G>A p.R945Qmissense 1VUS (1)0.000000
81. c.3742G>A p.G1248Rmissense 1VUS (1)0.000033
82. c.1455A>T p.K485Nmissense 1VUS (1)0.000000
83. c.49C>T p.R17Wmissense 1VUS (1)0.000023
84. c.701C>A p.T234Nmissense 1Likely Pathogenic (1)0.000000
85. c.103C>T p.R35Wmissense 1VUS (1)0.000056
86. c.1756C>G p.P586Amissense 1Likely Pathogenic (1)0.000000
87. c.2654C>T p.T885Mmissense 1VUS (1)0.000022
88. c.3791G>A p.C1264Ymissense 1VUS (1)0.000008
89. c.3G>C p.Met1?missense 1Likely Pathogenic (1)0.000000
90. c.2525A>G p.Y842Cmissense 1VUS (1)0.000000
91. c.3413G>C p.R1138Pmissense 1VUS (1)0.000000
92. c.2533C>T p.R845Cmissense 1VUS favour pathogenic (1)0.000000
93. c.566T>A p.V189Dmissense 1VUS (1)0.000000
94. c.3452C>T p.A1151Vmissense 1VUS (1)0.000078
95. c.223G>A p.D75Nmissense 1VUS favour pathogenic (1)0.000091
96. c.2993A>G p.Q998Rmissense 1VUS favour pathogenic (1)0.000000
97. c.3728C>G p.P1243Rmissense 1VUS (1)0.000000
98. c.146_148delTCA p.Ile49delinframe 1VUS (1)0.000039
99. c.2968C>G p.P990Amissense 1Likely Pathogenic (1)0.000000
100. c.481C>A p.P161Tmissense 1VUS favour pathogenic (1)0.000041
101. c.2518G>A p.V840Mmissense 1VUS (1)0.000016
102. c.3256T>C p.W1086Rmissense 1VUS (1)0.000000
103. c.1672G>A p.A558Tmissense 1VUS (1)0.000008
104. c.1097A>C p.Q366Pmissense 1VUS (1)0.000000
105. c.2312T>C p.V771Amissense 1VUS (1)0.000000
106. c.3083C>G p.T1028Smissense 1VUS (1)0.000000
107. c.3415G>A p.V1139Imissense 1VUS (1)0.000087
108. c.2528_2536delAGATGCGCG p.Glu843_Arg845delinframe 1Pathogenic (1)0.000000
109. c.2723A>G p.Y908Cmissense 1VUS (1)0.000062
110. c.1586C>G p.T529Smissense 1VUS favour pathogenic (1)0.000000
111. c.2436G>T p.K812Nmissense 1VUS (1)0.000000
112. c.3572C>T p.S1191Lmissense 1VUS (1)0.000016
113. c.1291G>A p.D431Nmissense 1VUS (1)0.000028
114. c.1591G>C p.G531Rmissense 1VUS favour pathogenic (1)0.000017
115. c.2503C>T p.R835Cmissense 1VUS (1)0.000024
116. c.188G>A p.R63Qmissense 1VUS (1)0.000039
117. c.1021G>C p.G341Rmissense 1VUS (1)0.000000
118. c.3797G>A p.C1266Ymissense 1Likely Pathogenic (1)0.000000
119. c.1471G>A p.V491Mmissense 1VUS (1)0.000058
120. c.1397T>A p.M466Kmissense 1VUS (1)0.000008
121. c.1231A>G p.I411Vmissense 1VUS (1)0.000000
122. c.2708G>A p.G903Dmissense 1Likely Pathogenic (1)0.000000
123. c.1960C>T p.R654Cmissense 1VUS favour benign (1)0.000008
124. c.241G>T p.V81Fmissense 1VUS (1)0.000000
125. c.932C>T p.S311Lmissense 1VUS (1)0.000000
126. c.3364A>T p.T1122Smissense 1Likely Pathogenic (1)0.000000
127. c.365C>A p.A122Dmissense 1VUS (1)0.000000
128. c.2828G>A p.R943Qmissense 1VUS (1)0.000025
129. c.104G>A p.R35Qmissense 1VUS (1)0.000079
130. c.3548T>G p.F1183Cmissense 1Likely Pathogenic (1)0.000000
131. c.451G>A p.D151Nmissense 1VUS (1)0.000041
132. c.1505G>T p.R502Lmissense 1VUS favour pathogenic (1)0.000000
133. c.436A>C p.T146Pmissense 1VUS (1)0.000000
134. c.290C>T p.A97Vmissense 1VUS favour pathogenic (1)0.000000
135. c.326C>T p.A109Vmissense 1VUS (1)0.000000
136. c.1188G>T p.W396Cmissense 1VUS (1)0.000000
137. c.2198G>A p.R733Hmissense 1VUS (1)0.000034
138. c.3656T>C p.L1219Pmissense 1VUS (1)0.000000
139. c.931T>A p.S311Tmissense 1VUS (1)0.000000
140. c.3316G>A p.D1106Nmissense 1VUS (1)0.000061
141. c.1343T>C p.F448Smissense 1Likely Pathogenic (1)0.000000
142. c.631G>A p.D211Nmissense 1VUS (1)0.000009
143. c.2265C>A p.N755Kmissense 1Pathogenic (1)0.000000
144. c.1112C>T p.P371Lmissense 1VUS (1)0.000028
145. c.2953A>G p.K985Emissense 1Pathogenic (1)0.000000
146. c.799C>G p.L267Vmissense 1VUS (1)0.000080
147. c.3614G>C p.R1205Pmissense 1Likely Pathogenic (1)0.000000
148. c.1778C>T p.S593Fmissense 1VUS favour pathogenic (1)0.000034
149. c.1731G>C p.W577Cmissense 1VUS (1)0.000000
150. c.148A>G p.S50Gmissense 1VUS (1)0.000038
151. c.713G>A p.R238Hmissense 1VUS (1)0.000074
152. c.2560A>G p.M854Vmissense 1VUS (1)0.000000
153. c.1080G>C p.K360Nmissense 1VUS (1)0.000000
154. c.3746G>T p.G1249Vmissense 1VUS (1)0.000000
155. c.3605G>A p.C1202Ymissense 1Likely Pathogenic (1)0.000000
156. c.3098G>A p.R1033Qmissense 1VUS (1)0.000000
157. c.2939G>A p.R980Hmissense 1VUS (1)0.000000
158. c.2909G>A p.R970Qmissense 1Likely Pathogenic (1)0.000032
159. c.518C>A p.T173Nmissense 1VUS (1)0.000000
160. c.1950C>G p.D650Emissense 1VUS (1)0.000000
161. c.3713T>C p.L1238Pmissense 1Likely Pathogenic (1)0.000000
162. c.1153G>A p.V385Mmissense 1VUS (1)0.000010
163. c.1789C>T p.R597Wmissense 1VUS (1)0.000038
164. c.3580G>A p.A1194Tmissense 1VUS (1)0.000008
165. c.187C>T p.R63Wmissense 1VUS (1)0.000077
166. c.3206C>A p.P1069Hmissense 1Likely Pathogenic (1)0.000000
167. c.994G>A p.E332Kmissense 1VUS (1)0.000009
168. c.2234A>G p.D745Gmissense 1VUS (1)0.000000
169. c.3739G>A p.D1247Nmissense 1VUS (1)0.000000
170. c.1433C>T p.S478Lmissense 1Likely Pathogenic (1)0.000017
171. c.3334_3351del p.Trp1112_Glu1117delinframe 1Likely Pathogenic (1)0.000000
172. c.1540A>G p.I514Vmissense 1VUS (1)0.000008
173. c.1174G>T p.A392Smissense 1VUS (1)0.000000
174. c.2381C>A p.P794Qmissense 1VUS (1)0.000000
175. c.1A>T p.Met1?missense 1Likely Pathogenic (1)0.000000
176. c.3049G>A p.E1017Kmissense 1VUS favour benign (1)0.000085
177. c.2938C>T p.R980Cmissense 1VUS (1)0.000062
178. c.2170C>T p.R724Wmissense 1VUS (1)0.000019
179. c.256_258del p.Ser86delinframe 1VUS (1)0.000000
180. c.1358C>T p.P453Lmissense 1VUS (1)0.000008
181. c.1535T>A p.L512Qmissense 1VUS favour pathogenic (1)0.000000
182. c.1294G>A p.A432Tmissense 1VUS (1)0.000037
183. c.2557G>A p.G853Smissense 1VUS (1)0.000008

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.