MYBPC3 truncating variants in HCM cohorts

The table below lists the 566 rare (MAF<0.0001 in ExAC) 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 0.09160 is compared with a background population rate of 0.00086, there is a statistically significant case excess of 0.09074 (p<0.0001), which suggests that approximately 560 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 class	LMM class	ExAC frequency
1.	c.3163A>T	p.K1055X	nonsense	4	Pathogenic (4)		0.000000
2.	c.2905C>T	p.Q969X	nonsense	5	Pathogenic (2)	Pathogenic (3)	0.000000
3.	c.932C>A	p.S311X	nonsense	2	Pathogenic (1)	Pathogenic (1)	0.000000
4.	c.1869C>A	p.C623X	nonsense	2		Pathogenic (2)	0.000000
5.	c.1405C>T	p.Q469X	nonsense	1	Pathogenic (1)		0.000000
6.	c.3181C>T	p.Q1061X	nonsense	4	Pathogenic (3)	Pathogenic (1)	0.000016
7.	c.3332_3335dupAGTG	p.W1112X	nonsense	1		Pathogenic (1)	0.000000
8.	c.2953A>T	p.K985X	nonsense	2	Pathogenic (1)	Pathogenic (1)	0.000000
9.	c.613C>T	p.Q205X	nonsense	1		Pathogenic (1)	0.000000
10.	c.3694A>T	p.K1232X	nonsense	1		Pathogenic (1)	0.000000
11.	c.2526C>G	p.Y842X	nonsense	2	Pathogenic (2)		0.000000
12.	c.3357C>A	p.Y1119X	nonsense	1	Pathogenic (1)		0.000000
13.	c.3697C>T	p.Q1233X	nonsense	13	Likely Pathogenic (4)	Pathogenic (9)	0.000008
14.	c.1458G>A	p.W486X	nonsense	1	Pathogenic (1)		0.000000
15.	c.1575T>G	p.Y525X	nonsense	1		Pathogenic (1)	0.000000
16.	c.3129C>A	p.Y1043X	nonsense	3	Pathogenic (3)		0.000000
17.	c.3335G>A	p.W1112X	nonsense	1		Pathogenic (1)	0.000000
18.	c.2454G>A	p.W818X	nonsense	4		Pathogenic (4)	0.000000
19.	c.1210C>T	p.Q404X	nonsense	2		Pathogenic (2)	0.000000
20.	c.3753T>G	p.Y1251X	nonsense	1		Pathogenic (1)	0.000000
21.	c.333_334insT	p.E112X	nonsense	1		Pathogenic (1)	0.000000
22.	c.999C>G	p.Y333X	nonsense	2		Pathogenic (2)	0.000000
23.	c.966G>A	p.W322X	nonsense	1		Pathogenic (1)	0.000000
24.	c.3286G>T	p.E1096X	nonsense	4	Pathogenic (3)	Pathogenic (1)	0.000000
25.	c.2584C>T	p.Q862X	nonsense	1	Pathogenic (1)		0.000000
26.	c.711C>A	p.Y237X	nonsense	1	Pathogenic (1)		0.000000
27.	c.2748G>A	p.W916X	nonsense	1	Pathogenic (1)		0.000000
28.	c.2670G>A	p.W890X	nonsense	7		Pathogenic (7)	0.000000
29.	c.2065C>T	p.Q689X	nonsense	1	Pathogenic (1)		0.000000
30.	c.1201C>T	p.Q401X	nonsense	1	Pathogenic (1)		0.000000
31.	c.3811C>T	p.R1271X	nonsense	2	VUS (1)	Pathogenic (1)	0.000025
32.	c.1000G>T	p.E334X	nonsense	1		Pathogenic (1)	0.000000
33.	c.747C>A	p.C249X	nonsense	2	Pathogenic (2)		0.000000
34.	c.2747G>A	p.W916X	nonsense	1		Pathogenic (1)	0.000000
35.	c.2965G>T	p.E989X	nonsense	1		Pathogenic (1)	0.000000
36.	c.3257G>A	p.W1086X	nonsense	1	Pathogenic (1)		0.000021
37.	c.2048G>A	p.W683X	nonsense	1		Pathogenic (1)	0.000000
38.	c.1457G>A	p.W486X	nonsense	1	Pathogenic (1)		0.000000
39.	c.1273C>T	p.Q425X	nonsense	2	Pathogenic (1)	Pathogenic (1)	0.000000
40.	c.484C>T	p.Q162X	nonsense	4	Pathogenic (4)		0.000000
41.	c.3408C>A	p.Y1136X	nonsense	4	Pathogenic (3)	Pathogenic (1)	0.000000
42.	c.126G>A	p.W42X	nonsense	2	Pathogenic (2)		0.000000
43.	c.2182G>T	p.E728X	nonsense	4		Pathogenic (4)	0.000000
44.	c.2920C>T	p.Q974X	nonsense	3		Pathogenic (3)	0.000000
45.	c.2541C>A	p.Y847X	nonsense	1		Pathogenic (1)	0.000000
46.	c.1303C>T	p.Q435X	nonsense	1	Pathogenic (1)		0.000000
47.	c.1693A>T	p.K565X	nonsense	1		Pathogenic (1)	0.000000
48.	c.2247C>A	p.Y749X	nonsense	1	Pathogenic (1)		0.000000
49.	c.1924C>T	p.Q642X	nonsense	1		Pathogenic (1)	0.000000
50.	c.2827C>T	p.R943X	nonsense	18	Pathogenic (11)	Pathogenic (7)	0.000017
51.	c.1156G>T	p.E386X	nonsense	1		Pathogenic (1)	0.000000
52.	c.3233G>A	p.W1078X	nonsense	3		Pathogenic (3)	0.000022
53.	c.1120C>T	p.Q374X	nonsense	1	Pathogenic (1)		0.000000
54.	c.2371C>T	p.Q791X	nonsense	1	Pathogenic (1)		0.000000
55.	c.2437A>T	p.K813X	nonsense	1		Pathogenic (1)	0.000000
56.	c.3253G>T	p.E1085X	nonsense	2	Pathogenic (1)	Pathogenic (1)	0.000000
57.	c.3825A>G	p.X1275TrpextX77	nonsense	1		Likely Pathogenic (1)	0.000000
58.	c.993_994insT	p.E332X	nonsense	1		Pathogenic (1)	0.000000
59.	c.2308+1G>A		essential splice site	3	Pathogenic (2)	Pathogenic (1)	0.000000
60.	c.1624+1G>A		essential splice site	1	Pathogenic (1)		0.000000
61.	c.506-1G>A		essential splice site	1	Pathogenic (1)		0.000000
62.	c.927-2A>G		essential splice site	10	Pathogenic (8)	Pathogenic (2)	0.000000
63.	c.2603-1G>C		essential splice site	1	Pathogenic (1)		0.000000
64.	c.1624+2T>C		essential splice site	1		Pathogenic (1)	0.000000
65.	c.1090+1G>A		essential splice site	2	Pathogenic (1)	Pathogenic (1)	0.000000
66.	c.1223+2T>C		essential splice site	1	Pathogenic (1)		0.000000
67.	c.26-2A>G		essential splice site	4		Pathogenic (4)	0.000051
68.	c.2905+1G>C		essential splice site	1		Pathogenic (1)	0.000000
69.	c.1351+1G>A		essential splice site	2	Pathogenic (1)	Pathogenic (1)	0.000000
70.	c.821+2T>G		essential splice site	1	Pathogenic (1)		0.000000
71.	c.2737+2T>A		essential splice site	1		Pathogenic (1)	0.000000
72.	c.3490+1G>A		essential splice site	1	Pathogenic (1)		0.000000
73.	c.2905+2dup		essential splice site	2	Likely Pathogenic (2)		0.000000
74.	c.3627+1G>A		essential splice site	8	Pathogenic (6)	Pathogenic (2)	0.000000
75.	c.2309-2A>G		essential splice site	9		Pathogenic (9)	0.000000
76.	c.2905+1G>A		essential splice site	7	Pathogenic (3)	Pathogenic (4)	0.000000
77.	c.1090+2T>C		essential splice site	1	Pathogenic (1)		0.000000
78.	c.2149-1G>A		essential splice site	1		Pathogenic (1)	0.000000
79.	c.655-2del		essential splice site	1	Pathogenic (1)		0.000000
80.	c.2906-2A>G		essential splice site	1		Pathogenic (1)	0.000000
81.	c.*26+2T>C		essential splice site	1	Likely Pathogenic (1)		0.000000
82.	c.3190+1G>A		essential splice site	3		Pathogenic (3)	0.000000
83.	c.2995-1G>A		essential splice site	1	Pathogenic (1)		0.000000
84.	c.2309-1G>A		essential splice site	3	Pathogenic (3)		0.000000
85.	c.2308+1G>T		essential splice site	1		Pathogenic (1)	0.000000
86.	c.1090+1G>T		essential splice site	2	Pathogenic (1)	Pathogenic (1)	0.000000
87.	c.1224-1G>T		essential splice site	1	Pathogenic (1)		0.000000
88.	c.2737+1G>C		essential splice site	1		Pathogenic (1)	0.000000
89.	c.1458-1G>A		essential splice site	1		Pathogenic (1)	0.000000
90.	c.821+2T>C		essential splice site	5	Pathogenic (4)	Pathogenic (1)	0.000000
91.	c.1898-1G>A		essential splice site	1	Pathogenic (1)		0.000000
92.	c.2603-2_2603-1delinsGA		essential splice site	1	Pathogenic (1)		0.000000
93.	c.2304_2308+2delCATCGGT		essential splice site	1	Pathogenic (1)		0.000000
94.	c.821+1G>A		essential splice site	5	Pathogenic (1)	Pathogenic (4)	0.000043
95.	c.3330+1G>C		essential splice site	1	Pathogenic (1)		0.000000
96.	c.3330+2T>G		essential splice site	11		Pathogenic (11)	0.000000
97.	c.1224-2A>G		essential splice site	1		Pathogenic (1)	0.000000
98.	c.655-1G>A		essential splice site	1		Pathogenic (1)	0.000000
99.	c.821+1G>C		essential splice site	1		Pathogenic (1)	0.000000
100.	c.3331-1G>A		essential splice site	1		Pathogenic (1)	0.000000
101.	c.506-1G>T		essential splice site	1		Pathogenic (1)	0.000000
102.	c.3627+1G>T		essential splice site	2	Pathogenic (2)		0.000000
103.	c.1928-2A>G		essential splice site	30	Pathogenic (10)	Pathogenic (20)	0.000000
104.	c.2738-2A>G		essential splice site	1	Pathogenic (1)		0.000000
105.	c.1351+2T>C		essential splice site	1		Pathogenic (1)	0.000000
106.	c.25+1G>A		essential splice site	2	Pathogenic (2)		0.000000
107.	c.3190+2T>G		essential splice site	9	Pathogenic (7)	Pathogenic (2)	0.000016
108.	c.772+1G>A		essential splice site	3	Pathogenic (1)	Pathogenic (2)	0.000000
109.	c.1897+1G>A		essential splice site	2		Pathogenic (2)	0.000000
110.	c.3491-2A>T		essential splice site	3		Pathogenic (3)	0.000000
111.	c.3815-1G>A		essential splice site	1		Pathogenic (1)	0.000000
112.	c.833delG	p.Gly278GlufsX22	frameshift	3	Pathogenic (2)	Pathogenic (1)	0.000000
113.	c.2610_2611insC	p.Ser871GlnfsX13	frameshift	1		Pathogenic (1)	0.000000
114.	c.3316del	p.Asp1106Thrfs*83	frameshift	1	Pathogenic (1)		0.000000
115.	c.743_746delACTG		frameshift	1	Pathogenic (1)		0.000000
116.	c.2789del	p.Leu930Argfs*2	frameshift	1	Pathogenic (1)		0.000000
117.	c.2054_2067+11del	p.Lys685Argfs*3	frameshift	1	Pathogenic (1)		0.000000
118.	c.1800delA		frameshift	1		Pathogenic (1)	0.000000
119.	c.2429_2503delins23	p.Arg810Profs*10	frameshift	1	Pathogenic (1)		0.000000
120.	c.2690_2696del	p.Gly897Glufs*25	frameshift	1	Pathogenic (1)		0.000000
121.	c.443dup	p.Ala149Serfs*4	frameshift	2	Pathogenic (2)		0.000000
122.	c.3476_3477delTT		frameshift	1		Pathogenic (1)	0.000000
123.	c.121dup	p.Arg41Profs*8	frameshift	1	Pathogenic (1)		0.000000
124.	c.2780_2781delCA		frameshift	1		Pathogenic (1)	0.000000
125.	c.1266_1267insTGAT	p.Ile423*	frameshift	1	Pathogenic (1)		0.000000
126.	c.1863delC	p.Phe621LeufsX42	frameshift	2		Pathogenic (2)	0.000000
127.	c.3192_3193insC	p.Lys1065GlnfsX12	frameshift	2		Pathogenic (2)	0.000000
128.	c.177dup	p.Glu60Argfs*53	frameshift	1	Pathogenic (1)		0.000000
129.	c.2311_2312insG	p.Val771GlyfsX62	frameshift	3		Pathogenic (3)	0.000000
130.	c.2556_2557delinsTCT	p.Gly853fs	frameshift	5	Pathogenic (4)	Pathogenic (1)	0.000000
131.	c.533delT	p.Val178GlyfsX7	frameshift	1		Pathogenic (1)	0.000000
132.	c.2267delC		frameshift	5	Pathogenic (5)		0.000000
133.	c.2040_2041insT	p.Val681CysfsX12	frameshift	1		Pathogenic (1)	0.000000
134.	c.2534_2538delGCGTC		frameshift	2	Pathogenic (1)	Pathogenic (1)	0.000000
135.	c.982delG		frameshift	1	Pathogenic (1)		0.000000
136.	c.2524dup	p.Tyr842Leufs*42	frameshift	2	Pathogenic (2)		0.000000
137.	c.2373_2374insG	p.Trp792ValfsTer41	frameshift	66	Pathogenic (40)	Pathogenic (26)	0.000037
138.	c.2149_2737del	p.Leu717Alafs*11	frameshift	1	Pathogenic (1)		0.000000
139.	c.2188del	p.Thr730Profs*24	frameshift	1	Pathogenic (1)		0.000000
140.	c.3776delA		frameshift	1		Pathogenic (1)	0.000000
141.	c.1359del	p.Val454Cysfs*12	frameshift	1	Pathogenic (1)		0.000000
142.	c.553_562del	p.Lys185Trpfs*12	frameshift	1	Pathogenic (1)		0.000000
143.	c.1569dup	p.His524Alafs*7	frameshift	1	Pathogenic (1)		0.000000
144.	c.1678delG	p.Asp560ThrfsX19	frameshift	1		Pathogenic (1)	0.000000
145.	c.3226_3227insT		frameshift	18	Pathogenic (12)	Pathogenic (6)	0.000000
146.	c.1699_1700delGA	p.Glu567GlyfsX4	frameshift	1		Pathogenic (1)	0.000000
147.	c.255del	p.Ser86Profs*10	frameshift	1	Pathogenic (1)		0.000000
148.	c.2524_2525insT	p.Tyr842LeufsX42	frameshift	1		Pathogenic (1)	0.000000
149.	c.1999_2000delinsG	p.Leu667AspfsX15	frameshift	2	Pathogenic (1)	Pathogenic (1)	0.000000
150.	c.431_432delGT	p.Gly144AlafsX8	frameshift	1		Pathogenic (1)	0.000000
151.	c.3166_3167insG	p.Ala1056GlyfsX9	frameshift	1		Pathogenic (1)	0.000000
152.	c.3617delG		frameshift	1	Pathogenic (1)		0.000000
153.	c.3624_3625insC	p.Lys1209GlnfsX33	frameshift	2		Pathogenic (2)	0.000000
154.	c.1377delC		frameshift	1	Pathogenic (1)		0.000000
155.	c.3297dup	p.Tyr1100Valfs*49	frameshift	1	Pathogenic (1)		0.000000
156.	c.1038_1042dupCGGCA		frameshift	2	Pathogenic (1)	Pathogenic (1)	0.000008
157.	c.1357_1358delCC		frameshift	2		Pathogenic (2)	0.000000
158.	c.1892delT		frameshift	1		Pathogenic (1)	0.000000
159.	c.1404del	p.Gln469Serfs*19	frameshift	1	Pathogenic (1)		0.000000
160.	c.2502del	p.Arg835Alafs*2	frameshift	1	Pathogenic (1)		0.000000
161.	c.100_110dup	p.Val38Serfs*5	frameshift	1	Pathogenic (1)		0.000000
162.	c.2943_2947delGACCA		frameshift	2		Pathogenic (2)	0.000000
163.	c.391dup	p.Ala131Glyfs*22	frameshift	1	Pathogenic (1)		0.000000
164.	c.1628delA		frameshift	1		Pathogenic (1)	0.000000
165.	c.3600_3609delCTGCTGTGCT		frameshift	3	Pathogenic (3)	Pathogenic (0)	0.000000
166.	c.1895delT	p.Met632ArgfsX31	frameshift	2		Pathogenic (2)	0.000000
167.	c.2394_2395insT	p.Gly799TrpfsX34	frameshift	1		Pathogenic (1)	0.000000
168.	c.2604_2605delinsA	p.S871fs	frameshift	10	Pathogenic (8)	Pathogenic (2)	0.000000
169.	c.3476_3479dupTTAT	p.Pro1161TyrfsX9	frameshift	1		Pathogenic (1)	0.000000
170.	c.436_437insA	p.Thr146AsnfsX7	frameshift	2		Pathogenic (2)	0.000000
171.	c.2163delC	p.Glu722ArgfsX32	frameshift	1		Pathogenic (1)	0.000000
172.	c.2517_2538del	p.Val840ThrfsX32	frameshift	1		Pathogenic (1)	0.000000
173.	c.2833_2834delCG		frameshift	1		Pathogenic (1)	0.000000
174.	c.811_817delTTCCGCC		frameshift	1	Pathogenic (1)		0.000000
175.	c.2807dup	p.Ala938Glyfs*113	frameshift	1	Pathogenic (1)		0.000000
176.	c.2512dup	p.Glu838Glyfs*46	frameshift	1	Pathogenic (1)		0.000000
177.	c.2558delG		frameshift	3	Pathogenic (1)	Pathogenic (2)	0.000000
178.	c.2718_2719dup	p.Glu907Glyfs*18	frameshift	1	Pathogenic (1)		0.000000
179.	c.3735delC		frameshift	1		Likely Pathogenic (1)	0.000000
180.	c.2161_2168del	p.Thr721Profs*23	frameshift	1	Pathogenic (1)		0.000000
181.	c.1523_1525delinsT	p.Gln508Leufs*22	frameshift	1	Pathogenic (1)		0.000000
182.	c.1021_1028del	p.Gly341*	frameshift	1	Pathogenic (1)		0.000000
183.	c.2490_2491insT	p.His831SerfsTer2	frameshift	8	Pathogenic (7)	Pathogenic (1)	0.000024
184.	c.1352_1353del	p.Glu451Alafs*23	frameshift	1	Pathogenic (1)		0.000000
185.	c.3068_3069insA	p.Asn1023LysfsX28	frameshift	1		Pathogenic (1)	0.000000
186.	c.211_212delinsTA	p.Val71*	frameshift	1	Pathogenic (1)		0.000000
187.	c.459delC		frameshift	2	Pathogenic (1)	Pathogenic (1)	0.000000
188.	c.177_187del	p.Glu60AlafsX49	frameshift	3	Pathogenic (2)	Pathogenic (1)	0.000000
189.	c.551_552insT	p.Lys185GlufsX56	frameshift	1		Pathogenic (1)	0.000000
190.	c.2113_2114insA	p.Thr705AsnfsX3	frameshift	1		Pathogenic (1)	0.000000
191.	c.3690_3691delCA	p.Phe1230LeufsX11	frameshift	1		Pathogenic (1)	0.000000
192.	c.2013_2016delinsGG	p.Pro672AspfsX20	frameshift	1		Pathogenic (1)	0.000000
193.	c.3605delG		frameshift	1	Pathogenic (1)		0.000000
194.	c.3043dup	p.Ala1015Glyfs*36	frameshift	1	Pathogenic (1)		0.000000
195.	c.2610delC		frameshift	5	Pathogenic (5)		0.000000
196.	c.2864_2865delCT		frameshift	14	Pathogenic (8)	Pathogenic (6)	0.000000
197.	c.3792_3793del	p.Cys1264*	frameshift	1	Likely Pathogenic (1)		0.000000
198.	c.1168delC		frameshift	1		Pathogenic (1)	0.000000
199.	c.3271del	p.Asp1091Metfs*98	frameshift	2	Pathogenic (2)		0.000000
200.	c.3288delG		frameshift	1		Pathogenic (1)	0.000000
201.	c.2545del	p.Val849Serfs*30	frameshift	3	Pathogenic (3)		0.000000
202.	c.2096delC		frameshift	19	Pathogenic (15)	Pathogenic (4)	0.000000
203.	c.1376_1377del	p.Pro459Leufs*15	frameshift	1	Pathogenic (1)		0.000000
204.	c.611_618delinsT	p.Gly204Valfs*94	frameshift	1	Pathogenic (1)		0.000000
205.	c.1797del	p.His599Glnfs*3	frameshift	1	Pathogenic (1)		0.000000
206.	c.913_914delTT		frameshift	5		Pathogenic (5)	0.000000
207.	c.3624delC		frameshift	3	Pathogenic (1)	Pathogenic (2)	0.000000
208.	c.731del	p.Lys244Argfs*56	frameshift	1	Pathogenic (1)		0.000000
209.	c.351_352del	p.Gly118Argfs*8	frameshift	1	Pathogenic (1)		0.000000
210.	c.2875_2876delAC	p.Thr959GlyfsX91	frameshift	1		Pathogenic (1)	0.000000
211.	c.3040delC	p.Leu1014TrpfsX6	frameshift	1		Pathogenic (1)	0.000000

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.