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.2459G>A	p.R820Q	missense	5	VUS	0.000016
21.	c.2308G>A	p.D770N	missense	5	Likely Pathogenic	0.000008
22.	c.2267delC		frameshift	5	Pathogenic	0.000000
23.	c.2610delC		frameshift	5	Pathogenic	0.000000
24.	c.3065G>C	p.R1022P	missense	5	Likely Pathogenic	0.000025
25.	c.1484G>A	p.R495Q	missense	4	Likely Pathogenic	0.000008
26.	c.2556_2557delinsTCT	p.Gly853fs	frameshift	4	Pathogenic	0.000000
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.3163A>T	p.K1055X	nonsense	4	Pathogenic	0.000000
30.	c.3798C>G	p.C1266W	missense	4	VUS	0.000000
31.	c.3697C>T	p.Q1233X	nonsense	4	Likely Pathogenic	0.000008
32.	c.484C>T	p.Q162X	nonsense	4	Pathogenic	0.000000
33.	c.2905+1G>A		essential splice site	3	Pathogenic	0.000000
34.	c.3181C>T	p.Q1061X	nonsense	3	Pathogenic	0.000016
35.	c.3277G>T	p.G1093C	missense	3	VUS	0.000020
36.	c.710A>C	p.Y237S	missense	3	Likely Pathogenic	0.000000
37.	c.1720C>T	p.R574W	missense	3	VUS	0.000054
38.	c.3600_3609delCTGCTGTGCT		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.3129C>A	p.Y1043X	nonsense	3	Pathogenic	0.000000
42.	c.3763G>A	p.A1255T	missense	3	VUS	0.000075
43.	c.2309-1G>A		essential splice site	3	Pathogenic	0.000000
44.	c.1123G>A	p.V375M	missense	3	VUS	0.000009
45.	c.2545del	p.Val849Serfs*30	frameshift	3	Pathogenic	0.000000
46.	c.3408C>A	p.Y1136X	nonsense	3	Pathogenic	0.000000
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.3582_3593delGGGCTACACTGC		inframe	2	Likely Pathogenic	0.000000
51.	c.3627+1G>T		essential splice site	2	Pathogenic	0.000000
52.	c.747C>A	p.C249X	nonsense	2	Pathogenic	0.000000
53.	c.25+1G>A		essential splice site	2	Pathogenic	0.000000
54.	c.1505G>A	p.R502Q	missense	2	Pathogenic	0.000000
55.	c.2573G>A	p.S858N	missense	2	Likely Pathogenic	0.000000
56.	c.3752A>G	p.Y1251C	missense	2	VUS	0.000000
57.	c.1828G>A	p.D610N	missense	2	VUS	0.000000
58.	c.2432A>G	p.K811R	missense	2	VUS	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.2905C>T	p.Q969X	nonsense	2	Pathogenic	0.000000
62.	c.1483C>T	p.R495W	missense	2	Likely Pathogenic	0.000000
63.	c.2300A>G	p.K767R	missense	2	VUS	0.000016
64.	c.3271del	p.Asp1091Metfs*98	frameshift	2	Pathogenic	0.000000
65.	c.177_187del	p.Glu60AlafsX49	frameshift	2	Pathogenic	0.000000
66.	c.3455_3466del	p.Ala1152_Lys1155del	inframe	2	Likely Pathogenic	0.000000
67.	c.557C>T	p.P186L	missense	2	VUS	0.000047
68.	c.2219G>C	p.G740A	missense	2	VUS	0.000000
69.	c.3005G>A	p.R1002Q	missense	2	VUS	0.000046
70.	c.2308+1G>A		essential splice site	2	Pathogenic	0.000000
71.	c.3751T>C	p.Y1251H	missense	2	VUS	0.000000
72.	c.1886T>C	p.L629P	missense	2	VUS	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.2526C>G	p.Y842X	nonsense	2	Pathogenic	0.000000
76.	c.1231A>G	p.I411V	missense	1	VUS	0.000000
77.	c.701C>A	p.T234N	missense	1	Likely 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.365C>A	p.A122D	missense	1	VUS	0.000000
82.	c.1213A>G	p.M405V	missense	1	VUS	0.000000
83.	c.211_212delinsTA	p.Val71*	frameshift	1	Pathogenic	0.000000
84.	c.1377delC		frameshift	1	Pathogenic	0.000000
85.	c.1037G>A	p.R346H	missense	1	VUS	0.000000
86.	c.1090+1G>A		essential splice site	1	Pathogenic	0.000000
87.	c.532G>A	p.V178M	missense	1	VUS	0.000020
88.	c.3614G>C	p.R1205P	missense	1	Likely Pathogenic	0.000000
89.	c.2198G>A	p.R733H	missense	1	VUS	0.000034
90.	c.*26+2T>C		essential splice site	1	Likely Pathogenic	0.000000
91.	c.188G>A	p.R63Q	missense	1	VUS	0.000039
92.	c.3043dup	p.Ala1015Glyfs*36	frameshift	1	Pathogenic	0.000000
93.	c.3617delG		frameshift	1	Pathogenic	0.000000
94.	c.2603-1G>C		essential splice site	1	Pathogenic	0.000000
95.	c.3330+1G>C		essential splice site	1	Pathogenic	0.000000
96.	c.1999_2000delinsG	p.Leu667AspfsX15	frameshift	1	Pathogenic	0.000000
97.	c.2748G>A	p.W916X	nonsense	1	Pathogenic	0.000000
98.	c.3739G>A	p.D1247N	missense	1	VUS	0.000000
99.	c.2249C>T	p.T750M	missense	1	Likely Pathogenic	0.000024
100.	c.2247C>A	p.Y749X	nonsense	1	Pathogenic	0.000000
101.	c.2429_2503delins23	p.Arg810Profs*10	frameshift	1	Pathogenic	0.000000
102.	c.3713T>C	p.L1238P	missense	1	Likely Pathogenic	0.000000
103.	c.1797del	p.His599Glnfs*3	frameshift	1	Pathogenic	0.000000
104.	c.2690_2696del	p.Gly897Glufs*25	frameshift	1	Pathogenic	0.000000
105.	c.1120C>T	p.Q374X	nonsense	1	Pathogenic	0.000000
106.	c.3316G>A	p.D1106N	missense	1	VUS	0.000061
107.	c.2065C>T	p.Q689X	nonsense	1	Pathogenic	0.000000
108.	c.1352_1353del	p.Glu451Alafs*23	frameshift	1	Pathogenic	0.000000
109.	c.1458G>A	p.W486X	nonsense	1	Pathogenic	0.000000
110.	c.3064C>T	p.R1022C	missense	1	VUS	0.000008
111.	c.1021_1028del	p.Gly341*	frameshift	1	Pathogenic	0.000000
112.	c.255del	p.Ser86Profs*10	frameshift	1	Pathogenic	0.000000
113.	c.1456T>G	p.W486G	missense	1	VUS	0.000000
114.	c.553_562del	p.Lys185Trpfs*12	frameshift	1	Pathogenic	0.000000
115.	c.1303C>T	p.Q435X	nonsense	1	Pathogenic	0.000000
116.	c.994G>A	p.E332K	missense	1	VUS	0.000009
117.	c.743_746delACTG		frameshift	1	Pathogenic	0.000000
118.	c.1112C>T	p.P371L	missense	1	VUS	0.000028
119.	c.121dup	p.Arg41Profs*8	frameshift	1	Pathogenic	0.000000
120.	c.148A>G	p.S50G	missense	1	VUS	0.000038
121.	c.772+1G>A		essential splice site	1	Pathogenic	0.000000
122.	c.2304_2308+2delCATCGGT		essential splice site	1	Pathogenic	0.000000
123.	c.2504G>T	p.R835L	missense	1	Likely Pathogenic	0.000074
124.	c.2030C>T	p.P677L	missense	1	VUS	0.000000
125.	c.2807dup	p.Ala938Glyfs*113	frameshift	1	Pathogenic	0.000000
126.	c.3206C>A	p.P1069H	missense	1	Likely Pathogenic	0.000000
127.	c.3357C>A	p.Y1119X	nonsense	1	Pathogenic	0.000000
128.	c.2718_2719dup	p.Glu907Glyfs*18	frameshift	1	Pathogenic	0.000000
129.	c.2371C>T	p.Q791X	nonsense	1	Pathogenic	0.000000
130.	c.1376_1377del	p.Pro459Leufs*15	frameshift	1	Pathogenic	0.000000
131.	c.2381C>A	p.P794Q	missense	1	VUS	0.000000
132.	c.3676C>T	p.R1226C	missense	1	VUS	0.000058
133.	c.3257G>A	p.W1086X	nonsense	1	Pathogenic	0.000021
134.	c.1569dup	p.His524Alafs*7	frameshift	1	Pathogenic	0.000000
135.	c.1201C>T	p.Q401X	nonsense	1	Pathogenic	0.000000
136.	c.2161_2168del	p.Thr721Profs*23	frameshift	1	Pathogenic	0.000000
137.	c.351_352del	p.Gly118Argfs*8	frameshift	1	Pathogenic	0.000000
138.	c.1224-1G>T		essential splice site	1	Pathogenic	0.000000
139.	c.1471G>A	p.V491M	missense	1	VUS	0.000058
140.	c.655-2del		essential splice site	1	Pathogenic	0.000000
141.	c.1080G>C	p.K360N	missense	1	VUS	0.000000
142.	c.1153G>A	p.V385M	missense	1	VUS	0.000010
143.	c.177dup	p.Glu60Argfs*53	frameshift	1	Pathogenic	0.000000
144.	c.844C>T	p.R282W	missense	1	Likely Pathogenic	0.000000
145.	c.1351+1G>A		essential splice site	1	Pathogenic	0.000000
146.	c.391dup	p.Ala131Glyfs*22	frameshift	1	Pathogenic	0.000000
147.	c.1021G>C	p.G341R	missense	1	VUS	0.000000
148.	c.506-1G>A		essential splice site	1	Pathogenic	0.000000
149.	c.932C>A	p.S311X	nonsense	1	Pathogenic	0.000000
150.	c.2534_2538delGCGTC		frameshift	1	Pathogenic	0.000000
151.	c.811_817delTTCCGCC		frameshift	1	Pathogenic	0.000000
152.	c.1841A>G	p.Y614C	missense	1	VUS	0.000000
153.	c.2449C>T	p.R817W	missense	1	VUS	0.000000
154.	c.2197C>T	p.R733C	missense	1	Likely Pathogenic	0.000085
155.	c.2968C>G	p.P990A	missense	1	Likely Pathogenic	0.000000
156.	c.1790G>A	p.R597Q	missense	1	VUS	0.000000
157.	c.3614G>A	p.R1205Q	missense	1	VUS	0.000016
158.	c.2584C>T	p.Q862X	nonsense	1	Pathogenic	0.000000
159.	c.3316del	p.Asp1106Thrfs*83	frameshift	1	Pathogenic	0.000000
160.	c.2738-2A>G		essential splice site	1	Pathogenic	0.000000
161.	c.2603-2_2603-1delinsGA		essential splice site	1	Pathogenic	0.000000
162.	c.3452C>T	p.A1151V	missense	1	VUS	0.000078
163.	c.1405C>T	p.Q469X	nonsense	1	Pathogenic	0.000000
164.	c.3572C>T	p.S1191L	missense	1	VUS	0.000016
165.	c.2502del	p.Arg835Alafs*2	frameshift	1	Pathogenic	0.000000
166.	c.1756C>G	p.P586A	missense	1	Likely Pathogenic	0.000000
167.	c.731del	p.Lys244Argfs*56	frameshift	1	Pathogenic	0.000000
168.	c.1457G>A	p.W486X	nonsense	1	Pathogenic	0.000000
169.	c.1685C>T	p.A562V	missense	1	VUS	0.000008
170.	c.1097A>C	p.Q366P	missense	1	VUS	0.000000
171.	c.1266_1267insTGAT	p.Ile423*	frameshift	1	Pathogenic	0.000000
172.	c.2909G>A	p.R970Q	missense	1	Likely Pathogenic	0.000032
173.	c.1433C>T	p.S478L	missense	1	Likely Pathogenic	0.000017
174.	c.3019T>C	p.W1007R	missense	1	VUS	0.000000
175.	c.1072G>A	p.D358N	missense	1	VUS	0.000008
176.	c.1A>T	p.Met1?	missense	1	Likely Pathogenic	0.000000
177.	c.821+2T>G		essential splice site	1	Pathogenic	0.000000
178.	c.2558delG		frameshift	1	Pathogenic	0.000000
179.	c.1273C>T	p.Q425X	nonsense	1	Pathogenic	0.000000
180.	c.241G>T	p.V81F	missense	1	VUS	0.000000
181.	c.821+1G>A		essential splice site	1	Pathogenic	0.000043
182.	c.982delG		frameshift	1	Pathogenic	0.000000
183.	c.711C>A	p.Y237X	nonsense	1	Pathogenic	0.000000
184.	c.1090+1G>T		essential splice site	1	Pathogenic	0.000000
185.	c.631G>A	p.D211N	missense	1	VUS	0.000009
186.	c.49C>T	p.R17W	missense	1	VUS	0.000023
187.	c.373G>T	p.A125S	missense	1	VUS	0.000000
188.	c.2503C>T	p.R835C	missense	1	VUS	0.000024
189.	c.3728C>G	p.P1243R	missense	1	VUS	0.000000
190.	c.3624delC		frameshift	1	Pathogenic	0.000000
191.	c.3334_3351del	p.Trp1112_Glu1117del	inframe	1	Likely Pathogenic	0.000000
192.	c.2789del	p.Leu930Argfs*2	frameshift	1	Pathogenic	0.000000
193.	c.2265C>A	p.N755K	missense	1	Pathogenic	0.000000
194.	c.3605delG		frameshift	1	Pathogenic	0.000000
195.	c.2512dup	p.Glu838Glyfs*46	frameshift	1	Pathogenic	0.000000
196.	c.2708G>A	p.G903D	missense	1	Likely Pathogenic	0.000000
197.	c.3490+1G>A		essential splice site	1	Pathogenic	0.000000
198.	c.2834G>A	p.R945Q	missense	1	VUS	0.000000
199.	c.3373G>A	p.V1125M	missense	1	VUS	0.000022
200.	c.2054_2067+11del	p.Lys685Argfs*3	frameshift	1	Pathogenic	0.000000
201.	c.1359del	p.Val454Cysfs*12	frameshift	1	Pathogenic	0.000000
202.	c.3656T>C	p.L1219P	missense	1	VUS	0.000000
203.	c.2953A>T	p.K985X	nonsense	1	Pathogenic	0.000000
204.	c.3253G>T	p.E1085X	nonsense	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.100_110dup	p.Val38Serfs*5	frameshift	1	Pathogenic	0.000000
208.	c.1591G>A	p.G531R	missense	1	Likely Pathogenic	0.000017
209.	c.1038_1042dupCGGCA		frameshift	1	Pathogenic	0.000008
210.	c.1291G>A	p.D431N	missense	1	VUS	0.000028
211.	c.256_258del	p.Ser86del	inframe	1	VUS	0.000000
212.	c.1223+2T>C		essential splice site	1	Pathogenic	0.000000
213.	c.2873C>T	p.T958I	missense	1	VUS	0.000065
214.	c.611_618delinsT	p.Gly204Valfs*94	frameshift	1	Pathogenic	0.000000
215.	c.1021G>A	p.G341S	missense	1	VUS	0.000025
216.	c.459delC		frameshift	1	Pathogenic	0.000000
217.	c.146_148delTCA	p.Ile49del	inframe	1	VUS	0.000039
218.	c.799C>G	p.L267V	missense	1	VUS	0.000080
219.	c.3792_3793del	p.Cys1264*	frameshift	1	Likely Pathogenic	0.000000
220.	c.2269G>A	p.V757M	missense	1	VUS	0.000066
221.	c.3256T>C	p.W1086R	missense	1	VUS	0.000000
222.	c.187C>T	p.R63W	missense	1	VUS	0.000077
223.	c.1828G>C	p.D610H	missense	1	VUS	0.000058
224.	c.3364A>T	p.T1122S	missense	1	Likely Pathogenic	0.000000
225.	c.1898-1G>A		essential splice site	1	Pathogenic	0.000000
226.	c.2149_2737del	p.Leu717Alafs*11	frameshift	1	Pathogenic	0.000000
227.	c.2953A>G	p.K985E	missense	1	Pathogenic	0.000000
228.	c.1789C>T	p.R597W	missense	1	VUS	0.000038
229.	c.3811C>T	p.R1271X	nonsense	1	VUS	0.000025
230.	c.3297dup	p.Tyr1100Valfs*49	frameshift	1	Pathogenic	0.000000
231.	c.2995-1G>A		essential splice site	1	Pathogenic	0.000000
232.	c.1731G>C	p.W577C	missense	1	VUS	0.000000
233.	c.2188del	p.Thr730Profs*24	frameshift	1	Pathogenic	0.000000
234.	c.1404del	p.Gln469Serfs*19	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.