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