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.2604_2605delinsA	p.S871fs	frameshift	8	Pathogenic	0.000000
16.	c.927-2A>G		essential splice site	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.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.1484G>A	p.R495Q	missense	4	Likely Pathogenic	0.000008
26.	c.821+2T>C		essential splice site	4	Pathogenic	0.000000
27.	c.442G>A	p.G148R	missense	4	Likely Pathogenic	0.000042
28.	c.3798C>G	p.C1266W	missense	4	VUS	0.000000
29.	c.3163A>T	p.K1055X	nonsense	4	Pathogenic	0.000000
30.	c.484C>T	p.Q162X	nonsense	4	Pathogenic	0.000000
31.	c.3697C>T	p.Q1233X	nonsense	4	Likely Pathogenic	0.000008
32.	c.2556_2557delinsTCT	p.Gly853fs	frameshift	4	Pathogenic	0.000000
33.	c.710A>C	p.Y237S	missense	3	Likely Pathogenic	0.000000
34.	c.3181C>T	p.Q1061X	nonsense	3	Pathogenic	0.000016
35.	c.1720C>T	p.R574W	missense	3	VUS	0.000054
36.	c.3286G>T	p.E1096X	nonsense	3	Pathogenic	0.000000
37.	c.2210C>T	p.T737M	missense	3	VUS	0.000050
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.2905+1G>A		essential splice site	3	Pathogenic	0.000000
41.	c.1123G>A	p.V375M	missense	3	VUS	0.000009
42.	c.3763G>A	p.A1255T	missense	3	VUS	0.000075
43.	c.3600_3609delCTGCTGTGCT		frameshift	3	Pathogenic	0.000000
44.	c.3408C>A	p.Y1136X	nonsense	3	Pathogenic	0.000000
45.	c.2545del	p.Val849Serfs*30	frameshift	3	Pathogenic	0.000000
46.	c.3277G>T	p.G1093C	missense	3	VUS	0.000020
47.	c.443dup	p.Ala149Serfs*4	frameshift	2	Pathogenic	0.000000
48.	c.818G>A	p.R273H	missense	2	VUS	0.000042
49.	c.3470C>T	p.P1157L	missense	2	VUS	0.000093
50.	c.2905C>T	p.Q969X	nonsense	2	Pathogenic	0.000000
51.	c.1828G>A	p.D610N	missense	2	VUS	0.000000
52.	c.2432A>G	p.K811R	missense	2	VUS	0.000000
53.	c.747C>A	p.C249X	nonsense	2	Pathogenic	0.000000
54.	c.25+1G>A		essential splice site	2	Pathogenic	0.000000
55.	c.1505G>A	p.R502Q	missense	2	Pathogenic	0.000000
56.	c.3752A>G	p.Y1251C	missense	2	VUS	0.000000
57.	c.3005G>A	p.R1002Q	missense	2	VUS	0.000046
58.	c.3627+1G>T		essential splice site	2	Pathogenic	0.000000
59.	c.2905+2dup		essential splice site	2	Likely Pathogenic	0.000000
60.	c.2524dup	p.Tyr842Leufs*42	frameshift	2	Pathogenic	0.000000
61.	c.2300A>G	p.K767R	missense	2	VUS	0.000016
62.	c.1483C>T	p.R495W	missense	2	Likely Pathogenic	0.000000
63.	c.3455_3466del	p.Ala1152_Lys1155del	inframe	2	Likely Pathogenic	0.000000
64.	c.557C>T	p.P186L	missense	2	VUS	0.000047
65.	c.3271del	p.Asp1091Metfs*98	frameshift	2	Pathogenic	0.000000
66.	c.177_187del	p.Glu60AlafsX49	frameshift	2	Pathogenic	0.000000
67.	c.2308+1G>A		essential splice site	2	Pathogenic	0.000000
68.	c.2219G>C	p.G740A	missense	2	VUS	0.000000
69.	c.3751T>C	p.Y1251H	missense	2	VUS	0.000000
70.	c.3582_3593delGGGCTACACTGC		inframe	2	Likely Pathogenic	0.000000
71.	c.1886T>C	p.L629P	missense	2	VUS	0.000000
72.	c.2526C>G	p.Y842X	nonsense	2	Pathogenic	0.000000
73.	c.126G>A	p.W42X	nonsense	2	Pathogenic	0.000000
74.	c.833delG	p.Gly278GlufsX22	frameshift	2	Pathogenic	0.000000
75.	c.2573G>A	p.S858N	missense	2	Likely Pathogenic	0.000000
76.	c.701C>A	p.T234N	missense	1	Likely Pathogenic	0.000000
77.	c.1999_2000delinsG	p.Leu667AspfsX15	frameshift	1	Pathogenic	0.000000
78.	c.1455A>T	p.K485N	missense	1	VUS	0.000000
79.	c.1624+1G>A		essential splice site	1	Pathogenic	0.000000
80.	c.1090+2T>C		essential splice site	1	Pathogenic	0.000000
81.	c.2249C>T	p.T750M	missense	1	Likely Pathogenic	0.000024
82.	c.365C>A	p.A122D	missense	1	VUS	0.000000
83.	c.1231A>G	p.I411V	missense	1	VUS	0.000000
84.	c.1377delC		frameshift	1	Pathogenic	0.000000
85.	c.1037G>A	p.R346H	missense	1	VUS	0.000000
86.	c.1213A>G	p.M405V	missense	1	VUS	0.000000
87.	c.211_212delinsTA	p.Val71*	frameshift	1	Pathogenic	0.000000
88.	c.532G>A	p.V178M	missense	1	VUS	0.000020
89.	c.3811C>T	p.R1271X	nonsense	1	VUS	0.000025
90.	c.1090+1G>A		essential splice site	1	Pathogenic	0.000000
91.	c.3614G>C	p.R1205P	missense	1	Likely Pathogenic	0.000000
92.	c.*26+2T>C		essential splice site	1	Likely Pathogenic	0.000000
93.	c.3614G>A	p.R1205Q	missense	1	VUS	0.000016
94.	c.188G>A	p.R63Q	missense	1	VUS	0.000039
95.	c.2603-1G>C		essential splice site	1	Pathogenic	0.000000
96.	c.3330+1G>C		essential splice site	1	Pathogenic	0.000000
97.	c.2748G>A	p.W916X	nonsense	1	Pathogenic	0.000000
98.	c.3316G>A	p.D1106N	missense	1	VUS	0.000061
99.	c.3739G>A	p.D1247N	missense	1	VUS	0.000000
100.	c.3043dup	p.Ala1015Glyfs*36	frameshift	1	Pathogenic	0.000000
101.	c.3572C>T	p.S1191L	missense	1	VUS	0.000016
102.	c.2504G>T	p.R835L	missense	1	Likely Pathogenic	0.000074
103.	c.2429_2503delins23	p.Arg810Profs*10	frameshift	1	Pathogenic	0.000000
104.	c.1797del	p.His599Glnfs*3	frameshift	1	Pathogenic	0.000000
105.	c.2690_2696del	p.Gly897Glufs*25	frameshift	1	Pathogenic	0.000000
106.	c.2304_2308+2delCATCGGT		essential splice site	1	Pathogenic	0.000000
107.	c.2247C>A	p.Y749X	nonsense	1	Pathogenic	0.000000
108.	c.2065C>T	p.Q689X	nonsense	1	Pathogenic	0.000000
109.	c.1352_1353del	p.Glu451Alafs*23	frameshift	1	Pathogenic	0.000000
110.	c.2030C>T	p.P677L	missense	1	VUS	0.000000
111.	c.1458G>A	p.W486X	nonsense	1	Pathogenic	0.000000
112.	c.1120C>T	p.Q374X	nonsense	1	Pathogenic	0.000000
113.	c.1021_1028del	p.Gly341*	frameshift	1	Pathogenic	0.000000
114.	c.255del	p.Ser86Profs*10	frameshift	1	Pathogenic	0.000000
115.	c.1456T>G	p.W486G	missense	1	VUS	0.000000
116.	c.553_562del	p.Lys185Trpfs*12	frameshift	1	Pathogenic	0.000000
117.	c.994G>A	p.E332K	missense	1	VUS	0.000009
118.	c.743_746delACTG		frameshift	1	Pathogenic	0.000000
119.	c.1112C>T	p.P371L	missense	1	VUS	0.000028
120.	c.121dup	p.Arg41Profs*8	frameshift	1	Pathogenic	0.000000
121.	c.1303C>T	p.Q435X	nonsense	1	Pathogenic	0.000000
122.	c.3624delC		frameshift	1	Pathogenic	0.000000
123.	c.3713T>C	p.L1238P	missense	1	Likely Pathogenic	0.000000
124.	c.148A>G	p.S50G	missense	1	VUS	0.000038
125.	c.772+1G>A		essential splice site	1	Pathogenic	0.000000
126.	c.3206C>A	p.P1069H	missense	1	Likely Pathogenic	0.000000
127.	c.3605delG		frameshift	1	Pathogenic	0.000000
128.	c.3357C>A	p.Y1119X	nonsense	1	Pathogenic	0.000000
129.	c.2807dup	p.Ala938Glyfs*113	frameshift	1	Pathogenic	0.000000
130.	c.2718_2719dup	p.Glu907Glyfs*18	frameshift	1	Pathogenic	0.000000
131.	c.2371C>T	p.Q791X	nonsense	1	Pathogenic	0.000000
132.	c.2909G>A	p.R970Q	missense	1	Likely Pathogenic	0.000032
133.	c.2534_2538delGCGTC		frameshift	1	Pathogenic	0.000000
134.	c.3064C>T	p.R1022C	missense	1	VUS	0.000008
135.	c.2197C>T	p.R733C	missense	1	Likely Pathogenic	0.000085
136.	c.1569dup	p.His524Alafs*7	frameshift	1	Pathogenic	0.000000
137.	c.2558delG		frameshift	1	Pathogenic	0.000000
138.	c.1201C>T	p.Q401X	nonsense	1	Pathogenic	0.000000
139.	c.2161_2168del	p.Thr721Profs*23	frameshift	1	Pathogenic	0.000000
140.	c.1841A>G	p.Y614C	missense	1	VUS	0.000000
141.	c.1376_1377del	p.Pro459Leufs*15	frameshift	1	Pathogenic	0.000000
142.	c.2449C>T	p.R817W	missense	1	VUS	0.000000
143.	c.2381C>A	p.P794Q	missense	1	VUS	0.000000
144.	c.1224-1G>T		essential splice site	1	Pathogenic	0.000000
145.	c.1471G>A	p.V491M	missense	1	VUS	0.000058
146.	c.655-2del		essential splice site	1	Pathogenic	0.000000
147.	c.1080G>C	p.K360N	missense	1	VUS	0.000000
148.	c.351_352del	p.Gly118Argfs*8	frameshift	1	Pathogenic	0.000000
149.	c.1790G>A	p.R597Q	missense	1	VUS	0.000000
150.	c.1153G>A	p.V385M	missense	1	VUS	0.000010
151.	c.177dup	p.Glu60Argfs*53	frameshift	1	Pathogenic	0.000000
152.	c.844C>T	p.R282W	missense	1	Likely Pathogenic	0.000000
153.	c.1351+1G>A		essential splice site	1	Pathogenic	0.000000
154.	c.391dup	p.Ala131Glyfs*22	frameshift	1	Pathogenic	0.000000
155.	c.1021G>C	p.G341R	missense	1	VUS	0.000000
156.	c.811_817delTTCCGCC		frameshift	1	Pathogenic	0.000000
157.	c.506-1G>A		essential splice site	1	Pathogenic	0.000000
158.	c.932C>A	p.S311X	nonsense	1	Pathogenic	0.000000
159.	c.3257G>A	p.W1086X	nonsense	1	Pathogenic	0.000021
160.	c.3676C>T	p.R1226C	missense	1	VUS	0.000058
161.	c.3452C>T	p.A1151V	missense	1	VUS	0.000078
162.	c.2968C>G	p.P990A	missense	1	Likely Pathogenic	0.000000
163.	c.2584C>T	p.Q862X	nonsense	1	Pathogenic	0.000000
164.	c.3316del	p.Asp1106Thrfs*83	frameshift	1	Pathogenic	0.000000
165.	c.2738-2A>G		essential splice site	1	Pathogenic	0.000000
166.	c.2953A>T	p.K985X	nonsense	1	Pathogenic	0.000000
167.	c.2873C>T	p.T958I	missense	1	VUS	0.000065
168.	c.1405C>T	p.Q469X	nonsense	1	Pathogenic	0.000000
169.	c.2503C>T	p.R835C	missense	1	VUS	0.000024
170.	c.2502del	p.Arg835Alafs*2	frameshift	1	Pathogenic	0.000000
171.	c.1756C>G	p.P586A	missense	1	Likely Pathogenic	0.000000
172.	c.2603-2_2603-1delinsGA		essential splice site	1	Pathogenic	0.000000
173.	c.1685C>T	p.A562V	missense	1	VUS	0.000008
174.	c.1097A>C	p.Q366P	missense	1	VUS	0.000000
175.	c.2265C>A	p.N755K	missense	1	Pathogenic	0.000000
176.	c.1266_1267insTGAT	p.Ile423*	frameshift	1	Pathogenic	0.000000
177.	c.731del	p.Lys244Argfs*56	frameshift	1	Pathogenic	0.000000
178.	c.1457G>A	p.W486X	nonsense	1	Pathogenic	0.000000
179.	c.1072G>A	p.D358N	missense	1	VUS	0.000008
180.	c.1A>T	p.Met1?	missense	1	Likely Pathogenic	0.000000
181.	c.821+2T>G		essential splice site	1	Pathogenic	0.000000
182.	c.1273C>T	p.Q425X	nonsense	1	Pathogenic	0.000000
183.	c.241G>T	p.V81F	missense	1	VUS	0.000000
184.	c.1433C>T	p.S478L	missense	1	Likely Pathogenic	0.000017
185.	c.821+1G>A		essential splice site	1	Pathogenic	0.000043
186.	c.982delG		frameshift	1	Pathogenic	0.000000
187.	c.711C>A	p.Y237X	nonsense	1	Pathogenic	0.000000
188.	c.1090+1G>T		essential splice site	1	Pathogenic	0.000000
189.	c.3490+1G>A		essential splice site	1	Pathogenic	0.000000
190.	c.49C>T	p.R17W	missense	1	VUS	0.000023
191.	c.3617delG		frameshift	1	Pathogenic	0.000000
192.	c.373G>T	p.A125S	missense	1	VUS	0.000000
193.	c.3728C>G	p.P1243R	missense	1	VUS	0.000000
194.	c.631G>A	p.D211N	missense	1	VUS	0.000009
195.	c.2789del	p.Leu930Argfs*2	frameshift	1	Pathogenic	0.000000
196.	c.3373G>A	p.V1125M	missense	1	VUS	0.000022
197.	c.2995-1G>A		essential splice site	1	Pathogenic	0.000000
198.	c.3334_3351del	p.Trp1112_Glu1117del	inframe	1	Likely Pathogenic	0.000000
199.	c.2512dup	p.Glu838Glyfs*46	frameshift	1	Pathogenic	0.000000
200.	c.3019T>C	p.W1007R	missense	1	VUS	0.000000
201.	c.2708G>A	p.G903D	missense	1	Likely Pathogenic	0.000000
202.	c.2834G>A	p.R945Q	missense	1	VUS	0.000000
203.	c.1828G>C	p.D610H	missense	1	VUS	0.000058
204.	c.1359del	p.Val454Cysfs*12	frameshift	1	Pathogenic	0.000000
205.	c.1523_1525delinsT	p.Gln508Leufs*22	frameshift	1	Pathogenic	0.000000
206.	c.1174G>T	p.A392S	missense	1	VUS	0.000000
207.	c.2269G>A	p.V757M	missense	1	VUS	0.000066
208.	c.2054_2067+11del	p.Lys685Argfs*3	frameshift	1	Pathogenic	0.000000
209.	c.1291G>A	p.D431N	missense	1	VUS	0.000028
210.	c.256_258del	p.Ser86del	inframe	1	VUS	0.000000
211.	c.1789C>T	p.R597W	missense	1	VUS	0.000038
212.	c.1223+2T>C		essential splice site	1	Pathogenic	0.000000
213.	c.611_618delinsT	p.Gly204Valfs*94	frameshift	1	Pathogenic	0.000000
214.	c.1898-1G>A		essential splice site	1	Pathogenic	0.000000
215.	c.100_110dup	p.Val38Serfs*5	frameshift	1	Pathogenic	0.000000
216.	c.1591G>A	p.G531R	missense	1	Likely Pathogenic	0.000017
217.	c.1038_1042dupCGGCA		frameshift	1	Pathogenic	0.000008
218.	c.1021G>A	p.G341S	missense	1	VUS	0.000025
219.	c.459delC		frameshift	1	Pathogenic	0.000000
220.	c.146_148delTCA	p.Ile49del	inframe	1	VUS	0.000039
221.	c.799C>G	p.L267V	missense	1	VUS	0.000080
222.	c.3256T>C	p.W1086R	missense	1	VUS	0.000000
223.	c.187C>T	p.R63W	missense	1	VUS	0.000077
224.	c.3253G>T	p.E1085X	nonsense	1	Pathogenic	0.000000
225.	c.3364A>T	p.T1122S	missense	1	Likely Pathogenic	0.000000
226.	c.3656T>C	p.L1219P	missense	1	VUS	0.000000
227.	c.3792_3793del	p.Cys1264*	frameshift	1	Likely Pathogenic	0.000000
228.	c.2953A>G	p.K985E	missense	1	Pathogenic	0.000000
229.	c.3297dup	p.Tyr1100Valfs*49	frameshift	1	Pathogenic	0.000000
230.	c.2149_2737del	p.Leu717Alafs*11	frameshift	1	Pathogenic	0.000000
231.	c.2188del	p.Thr730Profs*24	frameshift	1	Pathogenic	0.000000
232.	c.1404del	p.Gln469Serfs*19	frameshift	1	Pathogenic	0.000000
233.	c.2198G>A	p.R733H	missense	1	VUS	0.000034
234.	c.1731G>C	p.W577C	missense	1	VUS	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.