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

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.