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.927-2A>G		essential splice site	8	Pathogenic	0.000000
15.	c.2864_2865delCT		frameshift	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.1484G>A	p.R495Q	missense	4	Likely Pathogenic	0.000008
27.	c.821+2T>C		essential splice site	4	Pathogenic	0.000000
28.	c.442G>A	p.G148R	missense	4	Likely Pathogenic	0.000042
29.	c.3798C>G	p.C1266W	missense	4	VUS	0.000000
30.	c.3163A>T	p.K1055X	nonsense	4	Pathogenic	0.000000
31.	c.484C>T	p.Q162X	nonsense	4	Pathogenic	0.000000
32.	c.3697C>T	p.Q1233X	nonsense	4	Likely Pathogenic	0.000008
33.	c.2309-1G>A		essential splice site	3	Pathogenic	0.000000
34.	c.2905+1G>A		essential splice site	3	Pathogenic	0.000000
35.	c.1123G>A	p.V375M	missense	3	VUS	0.000009
36.	c.3763G>A	p.A1255T	missense	3	VUS	0.000075
37.	c.3408C>A	p.Y1136X	nonsense	3	Pathogenic	0.000000
38.	c.3600_3609delCTGCTGTGCT		frameshift	3	Pathogenic	0.000000
39.	c.3277G>T	p.G1093C	missense	3	VUS	0.000020
40.	c.2545del	p.Val849Serfs*30	frameshift	3	Pathogenic	0.000000
41.	c.710A>C	p.Y237S	missense	3	Likely Pathogenic	0.000000
42.	c.3181C>T	p.Q1061X	nonsense	3	Pathogenic	0.000016
43.	c.1720C>T	p.R574W	missense	3	VUS	0.000054
44.	c.3286G>T	p.E1096X	nonsense	3	Pathogenic	0.000000
45.	c.2210C>T	p.T737M	missense	3	VUS	0.000050
46.	c.3129C>A	p.Y1043X	nonsense	3	Pathogenic	0.000000
47.	c.2526C>G	p.Y842X	nonsense	2	Pathogenic	0.000000
48.	c.1886T>C	p.L629P	missense	2	VUS	0.000000
49.	c.126G>A	p.W42X	nonsense	2	Pathogenic	0.000000
50.	c.833delG	p.Gly278GlufsX22	frameshift	2	Pathogenic	0.000000
51.	c.2573G>A	p.S858N	missense	2	Likely Pathogenic	0.000000
52.	c.443dup	p.Ala149Serfs*4	frameshift	2	Pathogenic	0.000000
53.	c.818G>A	p.R273H	missense	2	VUS	0.000042
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.25+1G>A		essential splice site	2	Pathogenic	0.000000
60.	c.1505G>A	p.R502Q	missense	2	Pathogenic	0.000000
61.	c.3752A>G	p.Y1251C	missense	2	VUS	0.000000
62.	c.3005G>A	p.R1002Q	missense	2	VUS	0.000046
63.	c.3627+1G>T		essential splice site	2	Pathogenic	0.000000
64.	c.2524dup	p.Tyr842Leufs*42	frameshift	2	Pathogenic	0.000000
65.	c.2905+2dup		essential splice site	2	Likely Pathogenic	0.000000
66.	c.2300A>G	p.K767R	missense	2	VUS	0.000016
67.	c.1483C>T	p.R495W	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.2308+1G>A		essential splice site	2	Pathogenic	0.000000
73.	c.2219G>C	p.G740A	missense	2	VUS	0.000000
74.	c.3751T>C	p.Y1251H	missense	2	VUS	0.000000
75.	c.3582_3593delGGGCTACACTGC		inframe	2	Likely Pathogenic	0.000000
76.	c.2512dup	p.Glu838Glyfs*46	frameshift	1	Pathogenic	0.000000
77.	c.3019T>C	p.W1007R	missense	1	VUS	0.000000
78.	c.2708G>A	p.G903D	missense	1	Likely Pathogenic	0.000000
79.	c.2834G>A	p.R945Q	missense	1	VUS	0.000000
80.	c.2269G>A	p.V757M	missense	1	VUS	0.000066
81.	c.2054_2067+11del	p.Lys685Argfs*3	frameshift	1	Pathogenic	0.000000
82.	c.1828G>C	p.D610H	missense	1	VUS	0.000058
83.	c.1359del	p.Val454Cysfs*12	frameshift	1	Pathogenic	0.000000
84.	c.1523_1525delinsT	p.Gln508Leufs*22	frameshift	1	Pathogenic	0.000000
85.	c.1174G>T	p.A392S	missense	1	VUS	0.000000
86.	c.100_110dup	p.Val38Serfs*5	frameshift	1	Pathogenic	0.000000
87.	c.1591G>A	p.G531R	missense	1	Likely Pathogenic	0.000017
88.	c.1038_1042dupCGGCA		frameshift	1	Pathogenic	0.000008
89.	c.1291G>A	p.D431N	missense	1	VUS	0.000028
90.	c.256_258del	p.Ser86del	inframe	1	VUS	0.000000
91.	c.1789C>T	p.R597W	missense	1	VUS	0.000038
92.	c.1223+2T>C		essential splice site	1	Pathogenic	0.000000
93.	c.611_618delinsT	p.Gly204Valfs*94	frameshift	1	Pathogenic	0.000000
94.	c.1898-1G>A		essential splice site	1	Pathogenic	0.000000
95.	c.1021G>A	p.G341S	missense	1	VUS	0.000025
96.	c.459delC		frameshift	1	Pathogenic	0.000000
97.	c.146_148delTCA	p.Ile49del	inframe	1	VUS	0.000039
98.	c.799C>G	p.L267V	missense	1	VUS	0.000080
99.	c.3792_3793del	p.Cys1264*	frameshift	1	Likely Pathogenic	0.000000
100.	c.3256T>C	p.W1086R	missense	1	VUS	0.000000
101.	c.187C>T	p.R63W	missense	1	VUS	0.000077
102.	c.3253G>T	p.E1085X	nonsense	1	Pathogenic	0.000000
103.	c.3364A>T	p.T1122S	missense	1	Likely Pathogenic	0.000000
104.	c.3656T>C	p.L1219P	missense	1	VUS	0.000000
105.	c.2149_2737del	p.Leu717Alafs*11	frameshift	1	Pathogenic	0.000000
106.	c.2953A>G	p.K985E	missense	1	Pathogenic	0.000000
107.	c.3297dup	p.Tyr1100Valfs*49	frameshift	1	Pathogenic	0.000000
108.	c.2198G>A	p.R733H	missense	1	VUS	0.000034
109.	c.1731G>C	p.W577C	missense	1	VUS	0.000000
110.	c.2188del	p.Thr730Profs*24	frameshift	1	Pathogenic	0.000000
111.	c.1404del	p.Gln469Serfs*19	frameshift	1	Pathogenic	0.000000
112.	c.1231A>G	p.I411V	missense	1	VUS	0.000000
113.	c.701C>A	p.T234N	missense	1	Likely Pathogenic	0.000000
114.	c.1999_2000delinsG	p.Leu667AspfsX15	frameshift	1	Pathogenic	0.000000
115.	c.1455A>T	p.K485N	missense	1	VUS	0.000000
116.	c.1624+1G>A		essential splice site	1	Pathogenic	0.000000
117.	c.1090+2T>C		essential splice site	1	Pathogenic	0.000000
118.	c.2249C>T	p.T750M	missense	1	Likely Pathogenic	0.000024
119.	c.365C>A	p.A122D	missense	1	VUS	0.000000
120.	c.1213A>G	p.M405V	missense	1	VUS	0.000000
121.	c.211_212delinsTA	p.Val71*	frameshift	1	Pathogenic	0.000000
122.	c.1377delC		frameshift	1	Pathogenic	0.000000
123.	c.1037G>A	p.R346H	missense	1	VUS	0.000000
124.	c.3811C>T	p.R1271X	nonsense	1	VUS	0.000025
125.	c.1090+1G>A		essential splice site	1	Pathogenic	0.000000
126.	c.532G>A	p.V178M	missense	1	VUS	0.000020
127.	c.3614G>C	p.R1205P	missense	1	Likely Pathogenic	0.000000
128.	c.*26+2T>C		essential splice site	1	Likely Pathogenic	0.000000
129.	c.3614G>A	p.R1205Q	missense	1	VUS	0.000016
130.	c.188G>A	p.R63Q	missense	1	VUS	0.000039
131.	c.3043dup	p.Ala1015Glyfs*36	frameshift	1	Pathogenic	0.000000
132.	c.3572C>T	p.S1191L	missense	1	VUS	0.000016
133.	c.2603-1G>C		essential splice site	1	Pathogenic	0.000000
134.	c.3330+1G>C		essential splice site	1	Pathogenic	0.000000
135.	c.2748G>A	p.W916X	nonsense	1	Pathogenic	0.000000
136.	c.3316G>A	p.D1106N	missense	1	VUS	0.000061
137.	c.3739G>A	p.D1247N	missense	1	VUS	0.000000
138.	c.2304_2308+2delCATCGGT		essential splice site	1	Pathogenic	0.000000
139.	c.2247C>A	p.Y749X	nonsense	1	Pathogenic	0.000000
140.	c.2504G>T	p.R835L	missense	1	Likely Pathogenic	0.000074
141.	c.2429_2503delins23	p.Arg810Profs*10	frameshift	1	Pathogenic	0.000000
142.	c.1797del	p.His599Glnfs*3	frameshift	1	Pathogenic	0.000000
143.	c.2690_2696del	p.Gly897Glufs*25	frameshift	1	Pathogenic	0.000000
144.	c.1120C>T	p.Q374X	nonsense	1	Pathogenic	0.000000
145.	c.2065C>T	p.Q689X	nonsense	1	Pathogenic	0.000000
146.	c.1352_1353del	p.Glu451Alafs*23	frameshift	1	Pathogenic	0.000000
147.	c.2030C>T	p.P677L	missense	1	VUS	0.000000
148.	c.1458G>A	p.W486X	nonsense	1	Pathogenic	0.000000
149.	c.1021_1028del	p.Gly341*	frameshift	1	Pathogenic	0.000000
150.	c.255del	p.Ser86Profs*10	frameshift	1	Pathogenic	0.000000
151.	c.1456T>G	p.W486G	missense	1	VUS	0.000000
152.	c.553_562del	p.Lys185Trpfs*12	frameshift	1	Pathogenic	0.000000
153.	c.1303C>T	p.Q435X	nonsense	1	Pathogenic	0.000000
154.	c.994G>A	p.E332K	missense	1	VUS	0.000009
155.	c.743_746delACTG		frameshift	1	Pathogenic	0.000000
156.	c.1112C>T	p.P371L	missense	1	VUS	0.000028
157.	c.121dup	p.Arg41Profs*8	frameshift	1	Pathogenic	0.000000
158.	c.148A>G	p.S50G	missense	1	VUS	0.000038
159.	c.772+1G>A		essential splice site	1	Pathogenic	0.000000
160.	c.3624delC		frameshift	1	Pathogenic	0.000000
161.	c.3713T>C	p.L1238P	missense	1	Likely Pathogenic	0.000000
162.	c.2807dup	p.Ala938Glyfs*113	frameshift	1	Pathogenic	0.000000
163.	c.3206C>A	p.P1069H	missense	1	Likely Pathogenic	0.000000
164.	c.3605delG		frameshift	1	Pathogenic	0.000000
165.	c.3357C>A	p.Y1119X	nonsense	1	Pathogenic	0.000000
166.	c.3064C>T	p.R1022C	missense	1	VUS	0.000008
167.	c.2718_2719dup	p.Glu907Glyfs*18	frameshift	1	Pathogenic	0.000000
168.	c.2371C>T	p.Q791X	nonsense	1	Pathogenic	0.000000
169.	c.2909G>A	p.R970Q	missense	1	Likely Pathogenic	0.000032
170.	c.2534_2538delGCGTC		frameshift	1	Pathogenic	0.000000
171.	c.1841A>G	p.Y614C	missense	1	VUS	0.000000
172.	c.1376_1377del	p.Pro459Leufs*15	frameshift	1	Pathogenic	0.000000
173.	c.2449C>T	p.R817W	missense	1	VUS	0.000000
174.	c.2381C>A	p.P794Q	missense	1	VUS	0.000000
175.	c.2197C>T	p.R733C	missense	1	Likely Pathogenic	0.000085
176.	c.1569dup	p.His524Alafs*7	frameshift	1	Pathogenic	0.000000
177.	c.2558delG		frameshift	1	Pathogenic	0.000000
178.	c.1201C>T	p.Q401X	nonsense	1	Pathogenic	0.000000
179.	c.2161_2168del	p.Thr721Profs*23	frameshift	1	Pathogenic	0.000000
180.	c.351_352del	p.Gly118Argfs*8	frameshift	1	Pathogenic	0.000000
181.	c.1790G>A	p.R597Q	missense	1	VUS	0.000000
182.	c.1224-1G>T		essential splice site	1	Pathogenic	0.000000
183.	c.1471G>A	p.V491M	missense	1	VUS	0.000058
184.	c.655-2del		essential splice site	1	Pathogenic	0.000000
185.	c.1080G>C	p.K360N	missense	1	VUS	0.000000
186.	c.1153G>A	p.V385M	missense	1	VUS	0.000010
187.	c.177dup	p.Glu60Argfs*53	frameshift	1	Pathogenic	0.000000
188.	c.844C>T	p.R282W	missense	1	Likely Pathogenic	0.000000
189.	c.1351+1G>A		essential splice site	1	Pathogenic	0.000000
190.	c.391dup	p.Ala131Glyfs*22	frameshift	1	Pathogenic	0.000000
191.	c.1021G>C	p.G341R	missense	1	VUS	0.000000
192.	c.506-1G>A		essential splice site	1	Pathogenic	0.000000
193.	c.932C>A	p.S311X	nonsense	1	Pathogenic	0.000000
194.	c.811_817delTTCCGCC		frameshift	1	Pathogenic	0.000000
195.	c.3257G>A	p.W1086X	nonsense	1	Pathogenic	0.000021
196.	c.3676C>T	p.R1226C	missense	1	VUS	0.000058
197.	c.3452C>T	p.A1151V	missense	1	VUS	0.000078
198.	c.2953A>T	p.K985X	nonsense	1	Pathogenic	0.000000
199.	c.2968C>G	p.P990A	missense	1	Likely Pathogenic	0.000000
200.	c.2584C>T	p.Q862X	nonsense	1	Pathogenic	0.000000
201.	c.3316del	p.Asp1106Thrfs*83	frameshift	1	Pathogenic	0.000000
202.	c.2738-2A>G		essential splice site	1	Pathogenic	0.000000
203.	c.2603-2_2603-1delinsGA		essential splice site	1	Pathogenic	0.000000
204.	c.2873C>T	p.T958I	missense	1	VUS	0.000065
205.	c.1405C>T	p.Q469X	nonsense	1	Pathogenic	0.000000
206.	c.2503C>T	p.R835C	missense	1	VUS	0.000024
207.	c.2502del	p.Arg835Alafs*2	frameshift	1	Pathogenic	0.000000
208.	c.1756C>G	p.P586A	missense	1	Likely Pathogenic	0.000000
209.	c.731del	p.Lys244Argfs*56	frameshift	1	Pathogenic	0.000000
210.	c.1457G>A	p.W486X	nonsense	1	Pathogenic	0.000000
211.	c.1685C>T	p.A562V	missense	1	VUS	0.000008
212.	c.1097A>C	p.Q366P	missense	1	VUS	0.000000
213.	c.2265C>A	p.N755K	missense	1	Pathogenic	0.000000
214.	c.1266_1267insTGAT	p.Ile423*	frameshift	1	Pathogenic	0.000000
215.	c.1433C>T	p.S478L	missense	1	Likely Pathogenic	0.000017
216.	c.1072G>A	p.D358N	missense	1	VUS	0.000008
217.	c.1A>T	p.Met1?	missense	1	Likely Pathogenic	0.000000
218.	c.821+2T>G		essential splice site	1	Pathogenic	0.000000
219.	c.1273C>T	p.Q425X	nonsense	1	Pathogenic	0.000000
220.	c.241G>T	p.V81F	missense	1	VUS	0.000000
221.	c.821+1G>A		essential splice site	1	Pathogenic	0.000043
222.	c.982delG		frameshift	1	Pathogenic	0.000000
223.	c.711C>A	p.Y237X	nonsense	1	Pathogenic	0.000000
224.	c.1090+1G>T		essential splice site	1	Pathogenic	0.000000
225.	c.631G>A	p.D211N	missense	1	VUS	0.000009
226.	c.3490+1G>A		essential splice site	1	Pathogenic	0.000000
227.	c.49C>T	p.R17W	missense	1	VUS	0.000023
228.	c.3617delG		frameshift	1	Pathogenic	0.000000
229.	c.373G>T	p.A125S	missense	1	VUS	0.000000
230.	c.3728C>G	p.P1243R	missense	1	VUS	0.000000
231.	c.3334_3351del	p.Trp1112_Glu1117del	inframe	1	Likely Pathogenic	0.000000
232.	c.2789del	p.Leu930Argfs*2	frameshift	1	Pathogenic	0.000000
233.	c.3373G>A	p.V1125M	missense	1	VUS	0.000022
234.	c.2995-1G>A		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.