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