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.26-2A>G essential splice site 4Pathogenic0.000051
12. c.2905+1G>A essential splice site 4Pathogenic0.000000
13. c.2454G>A p.W818Xnonsense 4Pathogenic0.000000
14. c.2096delC frameshift 4Pathogenic0.000000
15. c.821+1G>A essential splice site 4Pathogenic0.000043
16. c.2182G>T p.E728Xnonsense 4Pathogenic0.000000
17. c.3233G>A p.W1078Xnonsense 3Pathogenic0.000022
18. c.3190+1G>A essential splice site 3Pathogenic0.000000
19. c.3491-2A>T essential splice site 3Pathogenic0.000000
20. c.2311_2312insG p.Val771GlyfsX62frameshift 3Pathogenic0.000000
21. c.2905C>T p.Q969Xnonsense 3Pathogenic0.000000
22. c.2920C>T p.Q974Xnonsense 3Pathogenic0.000000
23. c.772+1G>A essential splice site 2Pathogenic0.000000
24. c.3624delC frameshift 2Pathogenic0.000000
25. c.3190+2T>G essential splice site 2Pathogenic0.000016
26. c.1897+1G>A essential splice site 2Pathogenic0.000000
27. c.927-2A>G essential splice site 2Pathogenic0.000000
28. c.436_437insA p.Thr146AsnfsX7frameshift 2Pathogenic0.000000
29. c.1869C>A p.C623Xnonsense 2Pathogenic0.000000
30. c.1863delC p.Phe621LeufsX42frameshift 2Pathogenic0.000000
31. c.3192_3193insC p.Lys1065GlnfsX12frameshift 2Pathogenic0.000000
32. c.3627+1G>A essential splice site 2Pathogenic0.000000
33. c.1210C>T p.Q404Xnonsense 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.2558delG frameshift 2Pathogenic0.000000
41. c.3288delG frameshift 1Pathogenic0.000000
42. c.1693A>T p.K565Xnonsense 1Pathogenic0.000000
43. c.1168delC frameshift 1Pathogenic0.000000
44. c.1156G>T p.E386Xnonsense 1Pathogenic0.000000
45. c.431_432delGT p.Gly144AlafsX8frameshift 1Pathogenic0.000000
46. c.1924C>T p.Q642Xnonsense 1Pathogenic0.000000
47. c.966G>A p.W322Xnonsense 1Pathogenic0.000000
48. c.1351+2T>C essential splice site 1Pathogenic0.000000
49. c.2308+1G>T essential splice site 1Pathogenic0.000000
50. c.2875_2876delAC p.Thr959GlyfsX91frameshift 1Pathogenic0.000000
51. c.3825A>G p.X1275TrpextX77nonsense 1Likely Pathogenic0.000000
52. c.2437A>T p.K813Xnonsense 1Pathogenic0.000000
53. c.3253G>T p.E1085Xnonsense 1Pathogenic0.000000
54. c.3040delC p.Leu1014TrpfsX6frameshift 1Pathogenic0.000000
55. c.993_994insT p.E332Xnonsense 1Pathogenic0.000000
56. c.2610_2611insC p.Ser871GlnfsX13frameshift 1Pathogenic0.000000
57. c.1624+2T>C essential splice site 1Pathogenic0.000000
58. c.1090+1G>A essential splice site 1Pathogenic0.000000
59. c.1800delA frameshift 1Pathogenic0.000000
60. c.932C>A p.S311Xnonsense 1Pathogenic0.000000
61. c.3476_3477delTT frameshift 1Pathogenic0.000000
62. c.2517_2538del p.Val840ThrfsX32frameshift 1Pathogenic0.000000
63. c.2780_2781delCA frameshift 1Pathogenic0.000000
64. c.2905+1G>C essential splice site 1Pathogenic0.000000
65. c.1351+1G>A essential splice site 1Pathogenic0.000000
66. c.3181C>T p.Q1061Xnonsense 1Pathogenic0.000016
67. c.2833_2834delCG frameshift 1Pathogenic0.000000
68. c.2737+2T>A essential splice site 1Pathogenic0.000000
69. c.613C>T p.Q205Xnonsense 1Pathogenic0.000000
70. c.2556_2557delinsTCT p.Gly853fsframeshift 1Pathogenic0.000000
71. c.3332_3335dupAGTG p.W1112Xnonsense 1Pathogenic0.000000
72. c.2953A>T p.K985Xnonsense 1Pathogenic0.000000
73. c.2040_2041insT p.Val681CysfsX12frameshift 1Pathogenic0.000000
74. c.533delT p.Val178GlyfsX7frameshift 1Pathogenic0.000000
75. c.1575T>G p.Y525Xnonsense 1Pathogenic0.000000
76. c.3335G>A p.W1112Xnonsense 1Pathogenic0.000000
77. c.3776delA frameshift 1Pathogenic0.000000
78. c.506-1G>T essential splice site 1Pathogenic0.000000
79. c.1699_1700delGA p.Glu567GlyfsX4frameshift 1Pathogenic0.000000
80. c.2149-1G>A essential splice site 1Pathogenic0.000000
81. c.3753T>G p.Y1251Xnonsense 1Pathogenic0.000000
82. c.1678delG p.Asp560ThrfsX19frameshift 1Pathogenic0.000000
83. c.333_334insT p.E112Xnonsense 1Pathogenic0.000000
84. c.1999_2000delinsG p.Leu667AspfsX15frameshift 1Pathogenic0.000000
85. c.2906-2A>G essential splice site 1Pathogenic0.000000
86. c.2524_2525insT p.Tyr842LeufsX42frameshift 1Pathogenic0.000000
87. c.3166_3167insG p.Ala1056GlyfsX9frameshift 1Pathogenic0.000000
88. c.3286G>T p.E1096Xnonsense 1Pathogenic0.000000
89. c.1038_1042dupCGGCA frameshift 1Pathogenic0.000008
90. c.3811C>T p.R1271Xnonsense 1Pathogenic0.000025
91. c.3815-1G>A essential splice site 1Pathogenic0.000000
92. c.1892delT frameshift 1Pathogenic0.000000
93. c.1090+1G>T essential splice site 1Pathogenic0.000000
94. c.833delG p.Gly278GlufsX22frameshift 1Pathogenic0.000000
95. c.1000G>T p.E334Xnonsense 1Pathogenic0.000000
96. c.2308+1G>A essential splice site 1Pathogenic0.000000
97. c.2737+1G>C essential splice site 1Pathogenic0.000000
98. c.1628delA frameshift 1Pathogenic0.000000
99. c.1458-1G>A essential splice site 1Pathogenic0.000000
100. c.2394_2395insT p.Gly799TrpfsX34frameshift 1Pathogenic0.000000
101. c.2747G>A p.W916Xnonsense 1Pathogenic0.000000
102. c.2965G>T p.E989Xnonsense 1Pathogenic0.000000
103. c.821+2T>C essential splice site 1Pathogenic0.000000
104. c.3476_3479dupTTAT p.Pro1161TyrfsX9frameshift 1Pathogenic0.000000
105. c.2163delC p.Glu722ArgfsX32frameshift 1Pathogenic0.000000
106. c.2048G>A p.W683Xnonsense 1Pathogenic0.000000
107. c.3735delC frameshift 1Likely Pathogenic0.000000
108. c.1273C>T p.Q425Xnonsense 1Pathogenic0.000000
109. c.3694A>T p.K1232Xnonsense 1Pathogenic0.000000
110. c.2490_2491insT p.His831SerfsTer2frameshift 1Pathogenic0.000024
111. c.821+1G>C essential splice site 1Pathogenic0.000000
112. c.1224-2A>G essential splice site 1Pathogenic0.000000
113. c.3408C>A p.Y1136Xnonsense 1Pathogenic0.000000
114. c.655-1G>A essential splice site 1Pathogenic0.000000
115. c.177_187del p.Glu60AlafsX49frameshift 1Pathogenic0.000000
116. c.2534_2538delGCGTC frameshift 1Pathogenic0.000000
117. c.3068_3069insA p.Asn1023LysfsX28frameshift 1Pathogenic0.000000
118. c.459delC frameshift 1Pathogenic0.000000
119. c.2541C>A p.Y847Xnonsense 1Pathogenic0.000000
120. c.3331-1G>A essential splice site 1Pathogenic0.000000
121. c.2113_2114insA p.Thr705AsnfsX3frameshift 1Pathogenic0.000000
122. c.551_552insT p.Lys185GlufsX56frameshift 1Pathogenic0.000000
123. c.2013_2016delinsGG p.Pro672AspfsX20frameshift 1Pathogenic0.000000
124. c.3690_3691delCA p.Phe1230LeufsX11frameshift 1Pathogenic0.000000
125. c.3600_3609delCTGCTGTGCT frameshift 0Pathogenic0.000000

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.