MYBPC3 non-truncating variants in HCM cohorts


The table below lists the 338 rare (MAF<0.0001 in ExAC) non-truncating MYBPC3 variants identified in a cohort of 3267 HCM patients. When this rare variant frequency of 0.10346 is compared with a background population rate of 0.01884, there is a statistically significant case excess of 0.08462 (p<0.0001), which suggests that approximately 277 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.1504C>T p.R502Wmissense 59Pathogenic0.000024
2. c.772G>A p.E258Kmissense 47Pathogenic0.000039
3. c.1624G>C p.E542Qmissense 24Pathogenic0.000024
4. c.655G>C p.V219Lmissense 18Likely Pathogenic0.000000
5. c.2429G>A p.R810Hmissense 11VUS0.000033
6. c.3613C>T p.R1205Wmissense 10Likely Pathogenic0.000016
7. c.1483C>G p.R495Gmissense 10Likely Pathogenic0.000000
8. c.3771C>A p.N1257Kmissense 9Likely Pathogenic0.000000
9. c.2459G>A p.R820Qmissense 5VUS0.000016
10. c.2308G>A p.D770Nmissense 5Likely Pathogenic0.000008
11. c.3065G>C p.R1022Pmissense 5Likely Pathogenic0.000025
12. c.442G>A p.G148Rmissense 4Likely Pathogenic0.000042
13. c.1484G>A p.R495Qmissense 4Likely Pathogenic0.000008
14. c.3798C>G p.C1266Wmissense 4VUS0.000000
15. c.1123G>A p.V375Mmissense 3VUS0.000009
16. c.710A>C p.Y237Smissense 3Likely Pathogenic0.000000
17. c.3763G>A p.A1255Tmissense 3VUS0.000075
18. c.3277G>T p.G1093Cmissense 3VUS0.000020
19. c.2210C>T p.T737Mmissense 3VUS0.000050
20. c.1720C>T p.R574Wmissense 3VUS0.000054
21. c.1505G>A p.R502Qmissense 2Pathogenic0.000000
22. c.1886T>C p.L629Pmissense 2VUS0.000000
23. c.1483C>T p.R495Wmissense 2Likely Pathogenic0.000000
24. c.3752A>G p.Y1251Cmissense 2VUS0.000000
25. c.3455_3466del p.Ala1152_Lys1155delinframe 2Likely Pathogenic0.000000
26. c.3470C>T p.P1157Lmissense 2VUS0.000093
27. c.2432A>G p.K811Rmissense 2VUS0.000000
28. c.1828G>A p.D610Nmissense 2VUS0.000000
29. c.2219G>C p.G740Amissense 2VUS0.000000
30. c.3005G>A p.R1002Qmissense 2VUS0.000046
31. c.557C>T p.P186Lmissense 2VUS0.000047
32. c.3751T>C p.Y1251Hmissense 2VUS0.000000
33. c.2300A>G p.K767Rmissense 2VUS0.000016
34. c.818G>A p.R273Hmissense 2VUS0.000042
35. c.2573G>A p.S858Nmissense 2Likely Pathogenic0.000000
36. c.3582_3593delGGGCTACACTGC inframe 2Likely Pathogenic0.000000
37. c.1456T>G p.W486Gmissense 1VUS0.000000
38. c.1789C>T p.R597Wmissense 1VUS0.000038
39. c.532G>A p.V178Mmissense 1VUS0.000020
40. c.1213A>G p.M405Vmissense 1VUS0.000000
41. c.1021G>A p.G341Smissense 1VUS0.000025
42. c.3739G>A p.D1247Nmissense 1VUS0.000000
43. c.3206C>A p.P1069Hmissense 1Likely Pathogenic0.000000
44. c.1A>T p.Met1?missense 1Likely Pathogenic0.000000
45. c.1174G>T p.A392Smissense 1VUS0.000000
46. c.2381C>A p.P794Qmissense 1VUS0.000000
47. c.3019T>C p.W1007Rmissense 1VUS0.000000
48. c.3614G>A p.R1205Qmissense 1VUS0.000016
49. c.2873C>T p.T958Imissense 1VUS0.000065
50. c.2269G>A p.V757Mmissense 1VUS0.000066
51. c.3064C>T p.R1022Cmissense 1VUS0.000008
52. c.1471G>A p.V491Mmissense 1VUS0.000058
53. c.2197C>T p.R733Cmissense 1Likely Pathogenic0.000085
54. c.799C>G p.L267Vmissense 1VUS0.000080
55. c.1037G>A p.R346Hmissense 1VUS0.000000
56. c.1291G>A p.D431Nmissense 1VUS0.000028
57. c.3334_3351del p.Trp1112_Glu1117delinframe 1Likely Pathogenic0.000000
58. c.844C>T p.R282Wmissense 1Likely Pathogenic0.000000
59. c.188G>A p.R63Qmissense 1VUS0.000039
60. c.1455A>T p.K485Nmissense 1VUS0.000000
61. c.2834G>A p.R945Qmissense 1VUS0.000000
62. c.256_258del p.Ser86delinframe 1VUS0.000000
63. c.701C>A p.T234Nmissense 1Likely Pathogenic0.000000
64. c.3676C>T p.R1226Cmissense 1VUS0.000058
65. c.2504G>T p.R835Lmissense 1Likely Pathogenic0.000074
66. c.1112C>T p.P371Lmissense 1VUS0.000028
67. c.1433C>T p.S478Lmissense 1Likely Pathogenic0.000017
68. c.49C>T p.R17Wmissense 1VUS0.000023
69. c.994G>A p.E332Kmissense 1VUS0.000009
70. c.1153G>A p.V385Mmissense 1VUS0.000010
71. c.3728C>G p.P1243Rmissense 1VUS0.000000
72. c.1756C>G p.P586Amissense 1Likely Pathogenic0.000000
73. c.146_148delTCA p.Ile49delinframe 1VUS0.000039
74. c.2968C>G p.P990Amissense 1Likely Pathogenic0.000000
75. c.3713T>C p.L1238Pmissense 1Likely Pathogenic0.000000
76. c.1097A>C p.Q366Pmissense 1VUS0.000000
77. c.2449C>T p.R817Wmissense 1VUS0.000000
78. c.1841A>G p.Y614Cmissense 1VUS0.000000
79. c.3373G>A p.V1125Mmissense 1VUS0.000022
80. c.2265C>A p.N755Kmissense 1Pathogenic0.000000
81. c.2030C>T p.P677Lmissense 1VUS0.000000
82. c.1591G>A p.G531Rmissense 1Likely Pathogenic0.000017
83. c.1790G>A p.R597Qmissense 1VUS0.000000
84. c.1021G>C p.G341Rmissense 1VUS0.000000
85. c.187C>T p.R63Wmissense 1VUS0.000077
86. c.3256T>C p.W1086Rmissense 1VUS0.000000
87. c.631G>A p.D211Nmissense 1VUS0.000009
88. c.1231A>G p.I411Vmissense 1VUS0.000000
89. c.2708G>A p.G903Dmissense 1Likely Pathogenic0.000000
90. c.241G>T p.V81Fmissense 1VUS0.000000
91. c.3364A>T p.T1122Smissense 1Likely Pathogenic0.000000
92. c.3656T>C p.L1219Pmissense 1VUS0.000000
93. c.2909G>A p.R970Qmissense 1Likely Pathogenic0.000032
94. c.3452C>T p.A1151Vmissense 1VUS0.000078
95. c.2503C>T p.R835Cmissense 1VUS0.000024
96. c.2198G>A p.R733Hmissense 1VUS0.000034
97. c.1685C>T p.A562Vmissense 1VUS0.000008
98. c.1072G>A p.D358Nmissense 1VUS0.000008
99. c.373G>T p.A125Smissense 1VUS0.000000
100. c.2953A>G p.K985Emissense 1Pathogenic0.000000
101. c.365C>A p.A122Dmissense 1VUS0.000000
102. c.3614G>C p.R1205Pmissense 1Likely Pathogenic0.000000
103. c.1731G>C p.W577Cmissense 1VUS0.000000
104. c.148A>G p.S50Gmissense 1VUS0.000038
105. c.1080G>C p.K360Nmissense 1VUS0.000000
106. c.3572C>T p.S1191Lmissense 1VUS0.000016
107. c.2249C>T p.T750Mmissense 1Likely Pathogenic0.000024
108. c.1828G>C p.D610Hmissense 1VUS0.000058
109. c.3316G>A p.D1106Nmissense 1VUS0.000061

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.