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

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.