MYBPC3 truncating variants in HCM cohorts

The table below lists the 268 rare (MAF<0.0001 in ExAC) truncating MYBPC3 variants identified in a cohort of 2912 HCM patients. When this rare variant frequency of 0.09203 is compared with a background population rate of 0.00086, there is a statistically significant case excess of 0.09117 (p<0.0001), which suggests that approximately 265 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 (2912)LMM class ExAC frequency
1. c.2373_2374insG p.Trp792ValfsTer41frameshift 26Pathogenic0.000037
2. c.1928-2A>G essential splice site 20Pathogenic0.000000
3. c.3330+2T>G essential splice site 11Pathogenic0.000000
4. c.3697C>T p.Q1233Xnonsense 9Pathogenic0.000008
5. c.2309-2A>G essential splice site 9Pathogenic0.000000
6. c.2827C>T p.R943Xnonsense 7Pathogenic0.000017
7. c.2670G>A p.W890Xnonsense 7Pathogenic0.000000
8. c.2864_2865delCT frameshift 6Pathogenic0.000000
9. c.3226_3227insT frameshift 6Pathogenic0.000000
10. c.913_914delTT frameshift 5Pathogenic0.000000
11. c.821+1G>A essential splice site 4Pathogenic0.000043
12. c.2182G>T p.E728Xnonsense 4Pathogenic0.000000
13. c.2096delC frameshift 4Pathogenic0.000000
14. c.26-2A>G essential splice site 4Pathogenic0.000051
15. c.2454G>A p.W818Xnonsense 4Pathogenic0.000000
16. c.2905+1G>A essential splice site 4Pathogenic0.000000
17. c.2920C>T p.Q974Xnonsense 3Pathogenic0.000000
18. c.3233G>A p.W1078Xnonsense 3Pathogenic0.000022
19. c.3491-2A>T essential splice site 3Pathogenic0.000000
20. c.2905C>T p.Q969Xnonsense 3Pathogenic0.000000
21. c.2311_2312insG p.Val771GlyfsX62frameshift 3Pathogenic0.000000
22. c.3190+1G>A essential splice site 3Pathogenic0.000000
23. c.2558delG frameshift 2Pathogenic0.000000
24. c.3624delC frameshift 2Pathogenic0.000000
25. c.3190+2T>G essential splice site 2Pathogenic0.000016
26. c.772+1G>A essential splice site 2Pathogenic0.000000
27. c.1897+1G>A essential splice site 2Pathogenic0.000000
28. c.1869C>A p.C623Xnonsense 2Pathogenic0.000000
29. c.927-2A>G essential splice site 2Pathogenic0.000000
30. c.1863delC p.Phe621LeufsX42frameshift 2Pathogenic0.000000
31. c.3192_3193insC p.Lys1065GlnfsX12frameshift 2Pathogenic0.000000
32. c.1210C>T p.Q404Xnonsense 2Pathogenic0.000000
33. c.3627+1G>A essential splice site 2Pathogenic0.000000
34. c.3624_3625insC p.Lys1209GlnfsX33frameshift 2Pathogenic0.000000
35. c.999C>G p.Y333Xnonsense 2Pathogenic0.000000
36. c.1357_1358delCC frameshift 2Pathogenic0.000000
37. c.2943_2947delGACCA frameshift 2Pathogenic0.000000
38. c.1895delT p.Met632ArgfsX31frameshift 2Pathogenic0.000000
39. c.2604_2605delinsA p.S871fsframeshift 2Pathogenic0.000000
40. c.436_437insA p.Thr146AsnfsX7frameshift 2Pathogenic0.000000
41. c.2048G>A p.W683Xnonsense 1Pathogenic0.000000
42. c.3735delC frameshift 1Likely Pathogenic0.000000
43. c.821+1G>C essential splice site 1Pathogenic0.000000
44. c.1224-2A>G essential splice site 1Pathogenic0.000000
45. c.2833_2834delCG frameshift 1Pathogenic0.000000
46. c.3408C>A p.Y1136Xnonsense 1Pathogenic0.000000
47. c.655-1G>A essential splice site 1Pathogenic0.000000
48. c.2490_2491insT p.His831SerfsTer2frameshift 1Pathogenic0.000024
49. c.177_187del p.Glu60AlafsX49frameshift 1Pathogenic0.000000
50. c.3068_3069insA p.Asn1023LysfsX28frameshift 1Pathogenic0.000000
51. c.459delC frameshift 1Pathogenic0.000000
52. c.1273C>T p.Q425Xnonsense 1Pathogenic0.000000
53. c.3331-1G>A essential splice site 1Pathogenic0.000000
54. c.2113_2114insA p.Thr705AsnfsX3frameshift 1Pathogenic0.000000
55. c.551_552insT p.Lys185GlufsX56frameshift 1Pathogenic0.000000
56. c.2541C>A p.Y847Xnonsense 1Pathogenic0.000000
57. c.3690_3691delCA p.Phe1230LeufsX11frameshift 1Pathogenic0.000000
58. c.506-1G>T essential splice site 1Pathogenic0.000000
59. c.2013_2016delinsGG p.Pro672AspfsX20frameshift 1Pathogenic0.000000
60. c.3288delG frameshift 1Pathogenic0.000000
61. c.1693A>T p.K565Xnonsense 1Pathogenic0.000000
62. c.1924C>T p.Q642Xnonsense 1Pathogenic0.000000
63. c.1156G>T p.E386Xnonsense 1Pathogenic0.000000
64. c.1168delC frameshift 1Pathogenic0.000000
65. c.1351+2T>C essential splice site 1Pathogenic0.000000
66. c.3825A>G p.X1275TrpextX77nonsense 1Likely Pathogenic0.000000
67. c.2437A>T p.K813Xnonsense 1Pathogenic0.000000
68. c.3253G>T p.E1085Xnonsense 1Pathogenic0.000000
69. c.2875_2876delAC p.Thr959GlyfsX91frameshift 1Pathogenic0.000000
70. c.3815-1G>A essential splice site 1Pathogenic0.000000
71. c.3040delC p.Leu1014TrpfsX6frameshift 1Pathogenic0.000000
72. c.993_994insT p.E332Xnonsense 1Pathogenic0.000000
73. c.833delG p.Gly278GlufsX22frameshift 1Pathogenic0.000000
74. c.2610_2611insC p.Ser871GlnfsX13frameshift 1Pathogenic0.000000
75. c.1624+2T>C essential splice site 1Pathogenic0.000000
76. c.1090+1G>A essential splice site 1Pathogenic0.000000
77. c.2308+1G>A essential splice site 1Pathogenic0.000000
78. c.932C>A p.S311Xnonsense 1Pathogenic0.000000
79. c.2780_2781delCA frameshift 1Pathogenic0.000000
80. c.2905+1G>C essential splice site 1Pathogenic0.000000
81. c.1351+1G>A essential splice site 1Pathogenic0.000000
82. c.3476_3477delTT frameshift 1Pathogenic0.000000
83. c.1800delA frameshift 1Pathogenic0.000000
84. c.2737+2T>A essential splice site 1Pathogenic0.000000
85. c.3181C>T p.Q1061Xnonsense 1Pathogenic0.000016
86. c.2556_2557delinsTCT p.Gly853fsframeshift 1Pathogenic0.000000
87. c.3332_3335dupAGTG p.W1112Xnonsense 1Pathogenic0.000000
88. c.2953A>T p.K985Xnonsense 1Pathogenic0.000000
89. c.613C>T p.Q205Xnonsense 1Pathogenic0.000000
90. c.2040_2041insT p.Val681CysfsX12frameshift 1Pathogenic0.000000
91. c.533delT p.Val178GlyfsX7frameshift 1Pathogenic0.000000
92. c.3694A>T p.K1232Xnonsense 1Pathogenic0.000000
93. c.1575T>G p.Y525Xnonsense 1Pathogenic0.000000
94. c.2534_2538delGCGTC frameshift 1Pathogenic0.000000
95. c.3335G>A p.W1112Xnonsense 1Pathogenic0.000000
96. c.3776delA frameshift 1Pathogenic0.000000
97. c.1699_1700delGA p.Glu567GlyfsX4frameshift 1Pathogenic0.000000
98. c.2149-1G>A essential splice site 1Pathogenic0.000000
99. c.3753T>G p.Y1251Xnonsense 1Pathogenic0.000000
100. c.1678delG p.Asp560ThrfsX19frameshift 1Pathogenic0.000000
101. c.2906-2A>G essential splice site 1Pathogenic0.000000
102. c.2524_2525insT p.Tyr842LeufsX42frameshift 1Pathogenic0.000000
103. c.333_334insT p.E112Xnonsense 1Pathogenic0.000000
104. c.1999_2000delinsG p.Leu667AspfsX15frameshift 1Pathogenic0.000000
105. c.431_432delGT p.Gly144AlafsX8frameshift 1Pathogenic0.000000
106. c.3166_3167insG p.Ala1056GlyfsX9frameshift 1Pathogenic0.000000
107. c.966G>A p.W322Xnonsense 1Pathogenic0.000000
108. c.1038_1042dupCGGCA frameshift 1Pathogenic0.000008
109. c.1892delT frameshift 1Pathogenic0.000000
110. c.1090+1G>T essential splice site 1Pathogenic0.000000
111. c.3811C>T p.R1271Xnonsense 1Pathogenic0.000025
112. c.3286G>T p.E1096Xnonsense 1Pathogenic0.000000
113. c.1000G>T p.E334Xnonsense 1Pathogenic0.000000
114. c.2737+1G>C essential splice site 1Pathogenic0.000000
115. c.1628delA frameshift 1Pathogenic0.000000
116. c.2308+1G>T essential splice site 1Pathogenic0.000000
117. c.2394_2395insT p.Gly799TrpfsX34frameshift 1Pathogenic0.000000
118. c.2747G>A p.W916Xnonsense 1Pathogenic0.000000
119. c.1458-1G>A essential splice site 1Pathogenic0.000000
120. c.821+2T>C essential splice site 1Pathogenic0.000000
121. c.3476_3479dupTTAT p.Pro1161TyrfsX9frameshift 1Pathogenic0.000000
122. c.2965G>T p.E989Xnonsense 1Pathogenic0.000000
123. c.2517_2538del p.Val840ThrfsX32frameshift 1Pathogenic0.000000
124. c.2163delC p.Glu722ArgfsX32frameshift 1Pathogenic0.000000
125. c.3600_3609delCTGCTGTGCT frameshift 0Pathogenic0.000000


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.