MYBPC3 variants in HCM cohorts

The table below lists the 636 rare (MAF<0.0001 in ExAC) protein-altering MYBPC3 variants identified in a cohort of 3267 HCM patients. When this rare variant frequency of 0.19467 is compared with a background population rate of 0.01970, there is a statistically significant case excess of 0.17497 (p<0.0001), which suggests that approximately 572 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.R502W	missense	59	Pathogenic	0.000024
2.	c.772G>A	p.E258K	missense	47	Pathogenic	0.000039
3.	c.2373_2374insG	p.Trp792ValfsTer41	frameshift	40	Pathogenic	0.000037
4.	c.1624G>C	p.E542Q	missense	24	Pathogenic	0.000024
5.	c.655G>C	p.V219L	missense	18	Likely Pathogenic	0.000000
6.	c.2096delC		frameshift	15	Pathogenic	0.000000
7.	c.3226_3227insT		frameshift	12	Pathogenic	0.000000
8.	c.2827C>T	p.R943X	nonsense	11	Pathogenic	0.000017
9.	c.2429G>A	p.R810H	missense	11	VUS	0.000033
10.	c.1928-2A>G		essential splice site	10	Pathogenic	0.000000
11.	c.3613C>T	p.R1205W	missense	10	Likely Pathogenic	0.000016
12.	c.1483C>G	p.R495G	missense	10	Likely Pathogenic	0.000000
13.	c.3771C>A	p.N1257K	missense	9	Likely Pathogenic	0.000000
14.	c.2864_2865delCT		frameshift	8	Pathogenic	0.000000
15.	c.927-2A>G		essential splice site	8	Pathogenic	0.000000
16.	c.2604_2605delinsA	p.S871fs	frameshift	8	Pathogenic	0.000000
17.	c.2490_2491insT	p.His831SerfsTer2	frameshift	7	Pathogenic	0.000024
18.	c.3190+2T>G		essential splice site	7	Pathogenic	0.000016
19.	c.3627+1G>A		essential splice site	6	Pathogenic	0.000000
20.	c.2610delC		frameshift	5	Pathogenic	0.000000
21.	c.2267delC		frameshift	5	Pathogenic	0.000000
22.	c.3065G>C	p.R1022P	missense	5	Likely Pathogenic	0.000025
23.	c.2459G>A	p.R820Q	missense	5	VUS	0.000016
24.	c.2308G>A	p.D770N	missense	5	Likely Pathogenic	0.000008
25.	c.3163A>T	p.K1055X	nonsense	4	Pathogenic	0.000000
26.	c.484C>T	p.Q162X	nonsense	4	Pathogenic	0.000000
27.	c.3697C>T	p.Q1233X	nonsense	4	Likely Pathogenic	0.000008
28.	c.821+2T>C		essential splice site	4	Pathogenic	0.000000
29.	c.442G>A	p.G148R	missense	4	Likely Pathogenic	0.000042
30.	c.2556_2557delinsTCT	p.Gly853fs	frameshift	4	Pathogenic	0.000000
31.	c.3798C>G	p.C1266W	missense	4	VUS	0.000000
32.	c.1484G>A	p.R495Q	missense	4	Likely Pathogenic	0.000008
33.	c.3181C>T	p.Q1061X	nonsense	3	Pathogenic	0.000016
34.	c.1720C>T	p.R574W	missense	3	VUS	0.000054
35.	c.3129C>A	p.Y1043X	nonsense	3	Pathogenic	0.000000
36.	c.2309-1G>A		essential splice site	3	Pathogenic	0.000000
37.	c.2545del	p.Val849Serfs*30	frameshift	3	Pathogenic	0.000000
38.	c.3286G>T	p.E1096X	nonsense	3	Pathogenic	0.000000
39.	c.2210C>T	p.T737M	missense	3	VUS	0.000050
40.	c.710A>C	p.Y237S	missense	3	Likely Pathogenic	0.000000
41.	c.2905+1G>A		essential splice site	3	Pathogenic	0.000000
42.	c.1123G>A	p.V375M	missense	3	VUS	0.000009
43.	c.3763G>A	p.A1255T	missense	3	VUS	0.000075
44.	c.3408C>A	p.Y1136X	nonsense	3	Pathogenic	0.000000
45.	c.3600_3609delCTGCTGTGCT		frameshift	3	Pathogenic	0.000000
46.	c.3277G>T	p.G1093C	missense	3	VUS	0.000020
47.	c.2219G>C	p.G740A	missense	2	VUS	0.000000
48.	c.3470C>T	p.P1157L	missense	2	VUS	0.000093
49.	c.2905C>T	p.Q969X	nonsense	2	Pathogenic	0.000000
50.	c.747C>A	p.C249X	nonsense	2	Pathogenic	0.000000
51.	c.1828G>A	p.D610N	missense	2	VUS	0.000000
52.	c.2432A>G	p.K811R	missense	2	VUS	0.000000
53.	c.1505G>A	p.R502Q	missense	2	Pathogenic	0.000000
54.	c.25+1G>A		essential splice site	2	Pathogenic	0.000000
55.	c.3751T>C	p.Y1251H	missense	2	VUS	0.000000
56.	c.1886T>C	p.L629P	missense	2	VUS	0.000000
57.	c.3627+1G>T		essential splice site	2	Pathogenic	0.000000
58.	c.3005G>A	p.R1002Q	missense	2	VUS	0.000046
59.	c.833delG	p.Gly278GlufsX22	frameshift	2	Pathogenic	0.000000
60.	c.2300A>G	p.K767R	missense	2	VUS	0.000016
61.	c.1483C>T	p.R495W	missense	2	Likely Pathogenic	0.000000
62.	c.2308+1G>A		essential splice site	2	Pathogenic	0.000000
63.	c.818G>A	p.R273H	missense	2	VUS	0.000042
64.	c.3582_3593delGGGCTACACTGC		inframe	2	Likely Pathogenic	0.000000
65.	c.2526C>G	p.Y842X	nonsense	2	Pathogenic	0.000000
66.	c.3752A>G	p.Y1251C	missense	2	VUS	0.000000
67.	c.2524dup	p.Tyr842Leufs*42	frameshift	2	Pathogenic	0.000000
68.	c.126G>A	p.W42X	nonsense	2	Pathogenic	0.000000
69.	c.2905+2dup		essential splice site	2	Likely Pathogenic	0.000000
70.	c.2573G>A	p.S858N	missense	2	Likely Pathogenic	0.000000
71.	c.3271del	p.Asp1091Metfs*98	frameshift	2	Pathogenic	0.000000
72.	c.177_187del	p.Glu60AlafsX49	frameshift	2	Pathogenic	0.000000
73.	c.3455_3466del	p.Ala1152_Lys1155del	inframe	2	Likely Pathogenic	0.000000
74.	c.557C>T	p.P186L	missense	2	VUS	0.000047
75.	c.443dup	p.Ala149Serfs*4	frameshift	2	Pathogenic	0.000000
76.	c.1756C>G	p.P586A	missense	1	Likely Pathogenic	0.000000
77.	c.2603-2_2603-1delinsGA		essential splice site	1	Pathogenic	0.000000
78.	c.3811C>T	p.R1271X	nonsense	1	VUS	0.000025
79.	c.1090+1G>A		essential splice site	1	Pathogenic	0.000000
80.	c.1405C>T	p.Q469X	nonsense	1	Pathogenic	0.000000
81.	c.2502del	p.Arg835Alafs*2	frameshift	1	Pathogenic	0.000000
82.	c.1266_1267insTGAT	p.Ile423*	frameshift	1	Pathogenic	0.000000
83.	c.3614G>A	p.R1205Q	missense	1	VUS	0.000016
84.	c.1457G>A	p.W486X	nonsense	1	Pathogenic	0.000000
85.	c.3572C>T	p.S1191L	missense	1	VUS	0.000016
86.	c.1072G>A	p.D358N	missense	1	VUS	0.000008
87.	c.3316G>A	p.D1106N	missense	1	VUS	0.000061
88.	c.711C>A	p.Y237X	nonsense	1	Pathogenic	0.000000
89.	c.2304_2308+2delCATCGGT		essential splice site	1	Pathogenic	0.000000
90.	c.821+1G>A		essential splice site	1	Pathogenic	0.000043
91.	c.2504G>T	p.R835L	missense	1	Likely Pathogenic	0.000074
92.	c.982delG		frameshift	1	Pathogenic	0.000000
93.	c.2030C>T	p.P677L	missense	1	VUS	0.000000
94.	c.3728C>G	p.P1243R	missense	1	VUS	0.000000
95.	c.631G>A	p.D211N	missense	1	VUS	0.000009
96.	c.1120C>T	p.Q374X	nonsense	1	Pathogenic	0.000000
97.	c.49C>T	p.R17W	missense	1	VUS	0.000023
98.	c.373G>T	p.A125S	missense	1	VUS	0.000000
99.	c.1456T>G	p.W486G	missense	1	VUS	0.000000
100.	c.553_562del	p.Lys185Trpfs*12	frameshift	1	Pathogenic	0.000000
101.	c.3334_3351del	p.Trp1112_Glu1117del	inframe	1	Likely Pathogenic	0.000000
102.	c.1021_1028del	p.Gly341*	frameshift	1	Pathogenic	0.000000
103.	c.2789del	p.Leu930Argfs*2	frameshift	1	Pathogenic	0.000000
104.	c.255del	p.Ser86Profs*10	frameshift	1	Pathogenic	0.000000
105.	c.121dup	p.Arg41Profs*8	frameshift	1	Pathogenic	0.000000
106.	c.2834G>A	p.R945Q	missense	1	VUS	0.000000
107.	c.1303C>T	p.Q435X	nonsense	1	Pathogenic	0.000000
108.	c.2512dup	p.Glu838Glyfs*46	frameshift	1	Pathogenic	0.000000
109.	c.2708G>A	p.G903D	missense	1	Likely Pathogenic	0.000000
110.	c.1112C>T	p.P371L	missense	1	VUS	0.000028
111.	c.3713T>C	p.L1238P	missense	1	Likely Pathogenic	0.000000
112.	c.2054_2067+11del	p.Lys685Argfs*3	frameshift	1	Pathogenic	0.000000
113.	c.1359del	p.Val454Cysfs*12	frameshift	1	Pathogenic	0.000000
114.	c.3624delC		frameshift	1	Pathogenic	0.000000
115.	c.1523_1525delinsT	p.Gln508Leufs*22	frameshift	1	Pathogenic	0.000000
116.	c.1223+2T>C		essential splice site	1	Pathogenic	0.000000
117.	c.3605delG		frameshift	1	Pathogenic	0.000000
118.	c.2534_2538delGCGTC		frameshift	1	Pathogenic	0.000000
119.	c.3064C>T	p.R1022C	missense	1	VUS	0.000008
120.	c.1021G>A	p.G341S	missense	1	VUS	0.000025
121.	c.2909G>A	p.R970Q	missense	1	Likely Pathogenic	0.000032
122.	c.1201C>T	p.Q401X	nonsense	1	Pathogenic	0.000000
123.	c.146_148delTCA	p.Ile49del	inframe	1	VUS	0.000039
124.	c.799C>G	p.L267V	missense	1	VUS	0.000080
125.	c.1841A>G	p.Y614C	missense	1	VUS	0.000000
126.	c.2449C>T	p.R817W	missense	1	VUS	0.000000
127.	c.459delC		frameshift	1	Pathogenic	0.000000
128.	c.2197C>T	p.R733C	missense	1	Likely Pathogenic	0.000085
129.	c.2558delG		frameshift	1	Pathogenic	0.000000
130.	c.1080G>C	p.K360N	missense	1	VUS	0.000000
131.	c.3792_3793del	p.Cys1264*	frameshift	1	Likely Pathogenic	0.000000
132.	c.1790G>A	p.R597Q	missense	1	VUS	0.000000
133.	c.351_352del	p.Gly118Argfs*8	frameshift	1	Pathogenic	0.000000
134.	c.3256T>C	p.W1086R	missense	1	VUS	0.000000
135.	c.187C>T	p.R63W	missense	1	VUS	0.000077
136.	c.1471G>A	p.V491M	missense	1	VUS	0.000058
137.	c.655-2del		essential splice site	1	Pathogenic	0.000000
138.	c.3364A>T	p.T1122S	missense	1	Likely Pathogenic	0.000000
139.	c.391dup	p.Ala131Glyfs*22	frameshift	1	Pathogenic	0.000000
140.	c.3297dup	p.Tyr1100Valfs*49	frameshift	1	Pathogenic	0.000000
141.	c.2149_2737del	p.Leu717Alafs*11	frameshift	1	Pathogenic	0.000000
142.	c.1153G>A	p.V385M	missense	1	VUS	0.000010
143.	c.177dup	p.Glu60Argfs*53	frameshift	1	Pathogenic	0.000000
144.	c.2953A>G	p.K985E	missense	1	Pathogenic	0.000000
145.	c.1351+1G>A		essential splice site	1	Pathogenic	0.000000
146.	c.1404del	p.Gln469Serfs*19	frameshift	1	Pathogenic	0.000000
147.	c.1731G>C	p.W577C	missense	1	VUS	0.000000
148.	c.2188del	p.Thr730Profs*24	frameshift	1	Pathogenic	0.000000
149.	c.3452C>T	p.A1151V	missense	1	VUS	0.000078
150.	c.1231A>G	p.I411V	missense	1	VUS	0.000000
151.	c.3257G>A	p.W1086X	nonsense	1	Pathogenic	0.000021
152.	c.1455A>T	p.K485N	missense	1	VUS	0.000000
153.	c.3676C>T	p.R1226C	missense	1	VUS	0.000058
154.	c.2953A>T	p.K985X	nonsense	1	Pathogenic	0.000000
155.	c.1037G>A	p.R346H	missense	1	VUS	0.000000
156.	c.532G>A	p.V178M	missense	1	VUS	0.000020
157.	c.2873C>T	p.T958I	missense	1	VUS	0.000065
158.	c.2503C>T	p.R835C	missense	1	VUS	0.000024
159.	c.188G>A	p.R63Q	missense	1	VUS	0.000039
160.	c.731del	p.Lys244Argfs*56	frameshift	1	Pathogenic	0.000000
161.	c.3614G>C	p.R1205P	missense	1	Likely Pathogenic	0.000000
162.	c.1685C>T	p.A562V	missense	1	VUS	0.000008
163.	c.2265C>A	p.N755K	missense	1	Pathogenic	0.000000
164.	c.1097A>C	p.Q366P	missense	1	VUS	0.000000
165.	c.*26+2T>C		essential splice site	1	Likely Pathogenic	0.000000
166.	c.3739G>A	p.D1247N	missense	1	VUS	0.000000
167.	c.1273C>T	p.Q425X	nonsense	1	Pathogenic	0.000000
168.	c.241G>T	p.V81F	missense	1	VUS	0.000000
169.	c.3043dup	p.Ala1015Glyfs*36	frameshift	1	Pathogenic	0.000000
170.	c.1433C>T	p.S478L	missense	1	Likely Pathogenic	0.000017
171.	c.2603-1G>C		essential splice site	1	Pathogenic	0.000000
172.	c.3330+1G>C		essential splice site	1	Pathogenic	0.000000
173.	c.1A>T	p.Met1?	missense	1	Likely Pathogenic	0.000000
174.	c.821+2T>G		essential splice site	1	Pathogenic	0.000000
175.	c.2748G>A	p.W916X	nonsense	1	Pathogenic	0.000000
176.	c.1797del	p.His599Glnfs*3	frameshift	1	Pathogenic	0.000000
177.	c.2690_2696del	p.Gly897Glufs*25	frameshift	1	Pathogenic	0.000000
178.	c.1090+1G>T		essential splice site	1	Pathogenic	0.000000
179.	c.2247C>A	p.Y749X	nonsense	1	Pathogenic	0.000000
180.	c.2429_2503delins23	p.Arg810Profs*10	frameshift	1	Pathogenic	0.000000
181.	c.1458G>A	p.W486X	nonsense	1	Pathogenic	0.000000
182.	c.3490+1G>A		essential splice site	1	Pathogenic	0.000000
183.	c.2065C>T	p.Q689X	nonsense	1	Pathogenic	0.000000
184.	c.1352_1353del	p.Glu451Alafs*23	frameshift	1	Pathogenic	0.000000
185.	c.3617delG		frameshift	1	Pathogenic	0.000000
186.	c.3373G>A	p.V1125M	missense	1	VUS	0.000022
187.	c.2995-1G>A		essential splice site	1	Pathogenic	0.000000
188.	c.3019T>C	p.W1007R	missense	1	VUS	0.000000
189.	c.994G>A	p.E332K	missense	1	VUS	0.000009
190.	c.743_746delACTG		frameshift	1	Pathogenic	0.000000
191.	c.2269G>A	p.V757M	missense	1	VUS	0.000066
192.	c.1174G>T	p.A392S	missense	1	VUS	0.000000
193.	c.148A>G	p.S50G	missense	1	VUS	0.000038
194.	c.772+1G>A		essential splice site	1	Pathogenic	0.000000
195.	c.1828G>C	p.D610H	missense	1	VUS	0.000058
196.	c.1898-1G>A		essential splice site	1	Pathogenic	0.000000
197.	c.611_618delinsT	p.Gly204Valfs*94	frameshift	1	Pathogenic	0.000000
198.	c.3357C>A	p.Y1119X	nonsense	1	Pathogenic	0.000000
199.	c.1591G>A	p.G531R	missense	1	Likely Pathogenic	0.000017
200.	c.100_110dup	p.Val38Serfs*5	frameshift	1	Pathogenic	0.000000
201.	c.1038_1042dupCGGCA		frameshift	1	Pathogenic	0.000008
202.	c.2807dup	p.Ala938Glyfs*113	frameshift	1	Pathogenic	0.000000
203.	c.1291G>A	p.D431N	missense	1	VUS	0.000028
204.	c.1789C>T	p.R597W	missense	1	VUS	0.000038
205.	c.256_258del	p.Ser86del	inframe	1	VUS	0.000000
206.	c.3206C>A	p.P1069H	missense	1	Likely Pathogenic	0.000000
207.	c.2718_2719dup	p.Glu907Glyfs*18	frameshift	1	Pathogenic	0.000000
208.	c.2371C>T	p.Q791X	nonsense	1	Pathogenic	0.000000
209.	c.2161_2168del	p.Thr721Profs*23	frameshift	1	Pathogenic	0.000000
210.	c.1376_1377del	p.Pro459Leufs*15	frameshift	1	Pathogenic	0.000000
211.	c.2381C>A	p.P794Q	missense	1	VUS	0.000000
212.	c.1569dup	p.His524Alafs*7	frameshift	1	Pathogenic	0.000000
213.	c.1224-1G>T		essential splice site	1	Pathogenic	0.000000
214.	c.3253G>T	p.E1085X	nonsense	1	Pathogenic	0.000000
215.	c.3656T>C	p.L1219P	missense	1	VUS	0.000000
216.	c.1021G>C	p.G341R	missense	1	VUS	0.000000
217.	c.844C>T	p.R282W	missense	1	Likely Pathogenic	0.000000
218.	c.811_817delTTCCGCC		frameshift	1	Pathogenic	0.000000
219.	c.506-1G>A		essential splice site	1	Pathogenic	0.000000
220.	c.932C>A	p.S311X	nonsense	1	Pathogenic	0.000000
221.	c.2198G>A	p.R733H	missense	1	VUS	0.000034
222.	c.365C>A	p.A122D	missense	1	VUS	0.000000
223.	c.1999_2000delinsG	p.Leu667AspfsX15	frameshift	1	Pathogenic	0.000000
224.	c.701C>A	p.T234N	missense	1	Likely Pathogenic	0.000000
225.	c.1624+1G>A		essential splice site	1	Pathogenic	0.000000
226.	c.2249C>T	p.T750M	missense	1	Likely Pathogenic	0.000024
227.	c.1090+2T>C		essential splice site	1	Pathogenic	0.000000
228.	c.2738-2A>G		essential splice site	1	Pathogenic	0.000000
229.	c.1213A>G	p.M405V	missense	1	VUS	0.000000
230.	c.211_212delinsTA	p.Val71*	frameshift	1	Pathogenic	0.000000
231.	c.2968C>G	p.P990A	missense	1	Likely Pathogenic	0.000000
232.	c.1377delC		frameshift	1	Pathogenic	0.000000
233.	c.2584C>T	p.Q862X	nonsense	1	Pathogenic	0.000000
234.	c.3316del	p.Asp1106Thrfs*83	frameshift	1	Pathogenic	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.