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