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