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