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