MYBPC3 truncating variants in HCM cohorts


The table below lists the 298 rare (MAF<0.0001 in ExAC) truncating MYBPC3 variants identified in a cohort of 3267 HCM patients. When this rare variant frequency of 0.09122 is compared with a background population rate of 0.00086, there is a statistically significant case excess of 0.09036 (p<0.0001), which suggests that approximately 295 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 (3267)OMGL class ExAC frequency
1. c.2373_2374insG p.Trp792ValfsTer41frameshift 40Pathogenic0.000037
2. c.2096delC frameshift 15Pathogenic0.000000
3. c.3226_3227insT frameshift 12Pathogenic0.000000
4. c.2827C>T p.R943Xnonsense 11Pathogenic0.000017
5. c.1928-2A>G essential splice site 10Pathogenic0.000000
6. c.927-2A>G essential splice site 8Pathogenic0.000000
7. c.2864_2865delCT frameshift 8Pathogenic0.000000
8. c.2604_2605delinsA p.S871fsframeshift 8Pathogenic0.000000
9. c.3190+2T>G essential splice site 7Pathogenic0.000016
10. c.2490_2491insT p.His831SerfsTer2frameshift 7Pathogenic0.000024
11. c.3627+1G>A essential splice site 6Pathogenic0.000000
12. c.2610delC frameshift 5Pathogenic0.000000
13. c.2267delC frameshift 5Pathogenic0.000000
14. c.821+2T>C essential splice site 4Pathogenic0.000000
15. c.3163A>T p.K1055Xnonsense 4Pathogenic0.000000
16. c.484C>T p.Q162Xnonsense 4Pathogenic0.000000
17. c.2556_2557delinsTCT p.Gly853fsframeshift 4Pathogenic0.000000
18. c.3697C>T p.Q1233Xnonsense 4Likely Pathogenic0.000008
19. c.3181C>T p.Q1061Xnonsense 3Pathogenic0.000016
20. c.3129C>A p.Y1043Xnonsense 3Pathogenic0.000000
21. c.2545del p.Val849Serfs*30frameshift 3Pathogenic0.000000
22. c.3408C>A p.Y1136Xnonsense 3Pathogenic0.000000
23. c.2905+1G>A essential splice site 3Pathogenic0.000000
24. c.2309-1G>A essential splice site 3Pathogenic0.000000
25. c.3600_3609delCTGCTGTGCT frameshift 3Pathogenic0.000000
26. c.3286G>T p.E1096Xnonsense 3Pathogenic0.000000
27. c.2308+1G>A essential splice site 2Pathogenic0.000000
28. c.2905C>T p.Q969Xnonsense 2Pathogenic0.000000
29. c.2526C>G p.Y842Xnonsense 2Pathogenic0.000000
30. c.3627+1G>T essential splice site 2Pathogenic0.000000
31. c.3271del p.Asp1091Metfs*98frameshift 2Pathogenic0.000000
32. c.747C>A p.C249Xnonsense 2Pathogenic0.000000
33. c.126G>A p.W42Xnonsense 2Pathogenic0.000000
34. c.177_187del p.Glu60AlafsX49frameshift 2Pathogenic0.000000
35. c.25+1G>A essential splice site 2Pathogenic0.000000
36. c.833delG p.Gly278GlufsX22frameshift 2Pathogenic0.000000
37. c.2905+2dup essential splice site 2Likely Pathogenic0.000000
38. c.2524dup p.Tyr842Leufs*42frameshift 2Pathogenic0.000000
39. c.443dup p.Ala149Serfs*4frameshift 2Pathogenic0.000000
40. c.1377delC frameshift 1Pathogenic0.000000
41. c.1090+1G>A essential splice site 1Pathogenic0.000000
42. c.*26+2T>C essential splice site 1Likely Pathogenic0.000000
43. c.1898-1G>A essential splice site 1Pathogenic0.000000
44. c.811_817delTTCCGCC frameshift 1Pathogenic0.000000
45. c.2584C>T p.Q862Xnonsense 1Pathogenic0.000000
46. c.2748G>A p.W916Xnonsense 1Pathogenic0.000000
47. c.3297dup p.Tyr1100Valfs*49frameshift 1Pathogenic0.000000
48. c.1224-1G>T essential splice site 1Pathogenic0.000000
49. c.2502del p.Arg835Alafs*2frameshift 1Pathogenic0.000000
50. c.1457G>A p.W486Xnonsense 1Pathogenic0.000000
51. c.821+2T>G essential splice site 1Pathogenic0.000000
52. c.2161_2168del p.Thr721Profs*23frameshift 1Pathogenic0.000000
53. c.3624delC frameshift 1Pathogenic0.000000
54. c.1038_1042dupCGGCA frameshift 1Pathogenic0.000008
55. c.177dup p.Glu60Argfs*53frameshift 1Pathogenic0.000000
56. c.553_562del p.Lys185Trpfs*12frameshift 1Pathogenic0.000000
57. c.2558delG frameshift 1Pathogenic0.000000
58. c.459delC frameshift 1Pathogenic0.000000
59. c.1999_2000delinsG p.Leu667AspfsX15frameshift 1Pathogenic0.000000
60. c.1273C>T p.Q425Xnonsense 1Pathogenic0.000000
61. c.3330+1G>C essential splice site 1Pathogenic0.000000
62. c.2603-2_2603-1delinsGA essential splice site 1Pathogenic0.000000
63. c.711C>A p.Y237Xnonsense 1Pathogenic0.000000
64. c.2807dup p.Ala938Glyfs*113frameshift 1Pathogenic0.000000
65. c.1523_1525delinsT p.Gln508Leufs*22frameshift 1Pathogenic0.000000
66. c.2718_2719dup p.Glu907Glyfs*18frameshift 1Pathogenic0.000000
67. c.2247C>A p.Y749Xnonsense 1Pathogenic0.000000
68. c.1352_1353del p.Glu451Alafs*23frameshift 1Pathogenic0.000000
69. c.2512dup p.Glu838Glyfs*46frameshift 1Pathogenic0.000000
70. c.255del p.Ser86Profs*10frameshift 1Pathogenic0.000000
71. c.1376_1377del p.Pro459Leufs*15frameshift 1Pathogenic0.000000
72. c.655-2del essential splice site 1Pathogenic0.000000
73. c.3605delG frameshift 1Pathogenic0.000000
74. c.1120C>T p.Q374Xnonsense 1Pathogenic0.000000
75. c.100_110dup p.Val38Serfs*5frameshift 1Pathogenic0.000000
76. c.2953A>T p.K985Xnonsense 1Pathogenic0.000000
77. c.391dup p.Ala131Glyfs*22frameshift 1Pathogenic0.000000
78. c.3257G>A p.W1086Xnonsense 1Pathogenic0.000021
79. c.1351+1G>A essential splice site 1Pathogenic0.000000
80. c.772+1G>A essential splice site 1Pathogenic0.000000
81. c.3043dup p.Ala1015Glyfs*36frameshift 1Pathogenic0.000000
82. c.982delG frameshift 1Pathogenic0.000000
83. c.3792_3793del p.Cys1264*frameshift 1Likely Pathogenic0.000000
84. c.1797del p.His599Glnfs*3frameshift 1Pathogenic0.000000
85. c.2738-2A>G essential splice site 1Pathogenic0.000000
86. c.2371C>T p.Q791Xnonsense 1Pathogenic0.000000
87. c.3811C>T p.R1271Xnonsense 1VUS0.000025
88. c.2054_2067+11del p.Lys685Argfs*3frameshift 1Pathogenic0.000000
89. c.3617delG frameshift 1Pathogenic0.000000
90. c.1223+2T>C essential splice site 1Pathogenic0.000000
91. c.1405C>T p.Q469Xnonsense 1Pathogenic0.000000
92. c.1021_1028del p.Gly341*frameshift 1Pathogenic0.000000
93. c.2304_2308+2delCATCGGT essential splice site 1Pathogenic0.000000
94. c.1624+1G>A essential splice site 1Pathogenic0.000000
95. c.1090+1G>T essential splice site 1Pathogenic0.000000
96. c.821+1G>A essential splice site 1Pathogenic0.000043
97. c.2789del p.Leu930Argfs*2frameshift 1Pathogenic0.000000
98. c.3316del p.Asp1106Thrfs*83frameshift 1Pathogenic0.000000
99. c.2603-1G>C essential splice site 1Pathogenic0.000000
100. c.506-1G>A essential splice site 1Pathogenic0.000000
101. c.1458G>A p.W486Xnonsense 1Pathogenic0.000000
102. c.2188del p.Thr730Profs*24frameshift 1Pathogenic0.000000
103. c.1266_1267insTGAT p.Ile423*frameshift 1Pathogenic0.000000
104. c.2429_2503delins23 p.Arg810Profs*10frameshift 1Pathogenic0.000000
105. c.1090+2T>C essential splice site 1Pathogenic0.000000
106. c.211_212delinsTA p.Val71*frameshift 1Pathogenic0.000000
107. c.1359del p.Val454Cysfs*12frameshift 1Pathogenic0.000000
108. c.611_618delinsT p.Gly204Valfs*94frameshift 1Pathogenic0.000000
109. c.3490+1G>A essential splice site 1Pathogenic0.000000
110. c.3253G>T p.E1085Xnonsense 1Pathogenic0.000000
111. c.2995-1G>A essential splice site 1Pathogenic0.000000
112. c.2534_2538delGCGTC frameshift 1Pathogenic0.000000
113. c.1303C>T p.Q435Xnonsense 1Pathogenic0.000000
114. c.3357C>A p.Y1119Xnonsense 1Pathogenic0.000000
115. c.2690_2696del p.Gly897Glufs*25frameshift 1Pathogenic0.000000
116. c.743_746delACTG frameshift 1Pathogenic0.000000
117. c.932C>A p.S311Xnonsense 1Pathogenic0.000000
118. c.1569dup p.His524Alafs*7frameshift 1Pathogenic0.000000
119. c.2149_2737del p.Leu717Alafs*11frameshift 1Pathogenic0.000000
120. c.731del p.Lys244Argfs*56frameshift 1Pathogenic0.000000
121. c.2065C>T p.Q689Xnonsense 1Pathogenic0.000000
122. c.1201C>T p.Q401Xnonsense 1Pathogenic0.000000
123. c.351_352del p.Gly118Argfs*8frameshift 1Pathogenic0.000000
124. c.1404del p.Gln469Serfs*19frameshift 1Pathogenic0.000000
125. c.121dup p.Arg41Profs*8frameshift 1Pathogenic0.000000

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.