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

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.