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