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.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.3065G>C	p.R1022P	missense	5	Likely Pathogenic	0.000025
21.	c.2459G>A	p.R820Q	missense	5	VUS	0.000016
22.	c.2308G>A	p.D770N	missense	5	Likely Pathogenic	0.000008
23.	c.2610delC		frameshift	5	Pathogenic	0.000000
24.	c.2267delC		frameshift	5	Pathogenic	0.000000
25.	c.821+2T>C		essential splice site	4	Pathogenic	0.000000
26.	c.442G>A	p.G148R	missense	4	Likely Pathogenic	0.000042
27.	c.2556_2557delinsTCT	p.Gly853fs	frameshift	4	Pathogenic	0.000000
28.	c.3798C>G	p.C1266W	missense	4	VUS	0.000000
29.	c.1484G>A	p.R495Q	missense	4	Likely Pathogenic	0.000008
30.	c.3697C>T	p.Q1233X	nonsense	4	Likely Pathogenic	0.000008
31.	c.3163A>T	p.K1055X	nonsense	4	Pathogenic	0.000000
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.1123G>A	p.V375M	missense	3	VUS	0.000009
35.	c.3408C>A	p.Y1136X	nonsense	3	Pathogenic	0.000000
36.	c.3600_3609delCTGCTGTGCT		frameshift	3	Pathogenic	0.000000
37.	c.3277G>T	p.G1093C	missense	3	VUS	0.000020
38.	c.3181C>T	p.Q1061X	nonsense	3	Pathogenic	0.000016
39.	c.1720C>T	p.R574W	missense	3	VUS	0.000054
40.	c.3129C>A	p.Y1043X	nonsense	3	Pathogenic	0.000000
41.	c.2309-1G>A		essential splice site	3	Pathogenic	0.000000
42.	c.3763G>A	p.A1255T	missense	3	VUS	0.000075
43.	c.2545del	p.Val849Serfs*30	frameshift	3	Pathogenic	0.000000
44.	c.3286G>T	p.E1096X	nonsense	3	Pathogenic	0.000000
45.	c.2210C>T	p.T737M	missense	3	VUS	0.000050
46.	c.710A>C	p.Y237S	missense	3	Likely Pathogenic	0.000000
47.	c.2526C>G	p.Y842X	nonsense	2	Pathogenic	0.000000
48.	c.3627+1G>T		essential splice site	2	Pathogenic	0.000000
49.	c.3752A>G	p.Y1251C	missense	2	VUS	0.000000
50.	c.2905+2dup		essential splice site	2	Likely Pathogenic	0.000000
51.	c.2524dup	p.Tyr842Leufs*42	frameshift	2	Pathogenic	0.000000
52.	c.126G>A	p.W42X	nonsense	2	Pathogenic	0.000000
53.	c.2573G>A	p.S858N	missense	2	Likely Pathogenic	0.000000
54.	c.3271del	p.Asp1091Metfs*98	frameshift	2	Pathogenic	0.000000
55.	c.177_187del	p.Glu60AlafsX49	frameshift	2	Pathogenic	0.000000
56.	c.3455_3466del	p.Ala1152_Lys1155del	inframe	2	Likely Pathogenic	0.000000
57.	c.557C>T	p.P186L	missense	2	VUS	0.000047
58.	c.443dup	p.Ala149Serfs*4	frameshift	2	Pathogenic	0.000000
59.	c.2219G>C	p.G740A	missense	2	VUS	0.000000
60.	c.3470C>T	p.P1157L	missense	2	VUS	0.000093
61.	c.2905C>T	p.Q969X	nonsense	2	Pathogenic	0.000000
62.	c.747C>A	p.C249X	nonsense	2	Pathogenic	0.000000
63.	c.1828G>A	p.D610N	missense	2	VUS	0.000000
64.	c.2432A>G	p.K811R	missense	2	VUS	0.000000
65.	c.1505G>A	p.R502Q	missense	2	Pathogenic	0.000000
66.	c.25+1G>A		essential splice site	2	Pathogenic	0.000000
67.	c.3751T>C	p.Y1251H	missense	2	VUS	0.000000
68.	c.1886T>C	p.L629P	missense	2	VUS	0.000000
69.	c.3005G>A	p.R1002Q	missense	2	VUS	0.000046
70.	c.833delG	p.Gly278GlufsX22	frameshift	2	Pathogenic	0.000000
71.	c.2300A>G	p.K767R	missense	2	VUS	0.000016
72.	c.1483C>T	p.R495W	missense	2	Likely Pathogenic	0.000000
73.	c.2308+1G>A		essential splice site	2	Pathogenic	0.000000
74.	c.818G>A	p.R273H	missense	2	VUS	0.000042
75.	c.3582_3593delGGGCTACACTGC		inframe	2	Likely Pathogenic	0.000000
76.	c.743_746delACTG		frameshift	1	Pathogenic	0.000000
77.	c.3019T>C	p.W1007R	missense	1	VUS	0.000000
78.	c.994G>A	p.E332K	missense	1	VUS	0.000009
79.	c.3713T>C	p.L1238P	missense	1	Likely Pathogenic	0.000000
80.	c.2269G>A	p.V757M	missense	1	VUS	0.000066
81.	c.1174G>T	p.A392S	missense	1	VUS	0.000000
82.	c.148A>G	p.S50G	missense	1	VUS	0.000038
83.	c.772+1G>A		essential splice site	1	Pathogenic	0.000000
84.	c.1828G>C	p.D610H	missense	1	VUS	0.000058
85.	c.1898-1G>A		essential splice site	1	Pathogenic	0.000000
86.	c.611_618delinsT	p.Gly204Valfs*94	frameshift	1	Pathogenic	0.000000
87.	c.3357C>A	p.Y1119X	nonsense	1	Pathogenic	0.000000
88.	c.1591G>A	p.G531R	missense	1	Likely Pathogenic	0.000017
89.	c.100_110dup	p.Val38Serfs*5	frameshift	1	Pathogenic	0.000000
90.	c.1038_1042dupCGGCA		frameshift	1	Pathogenic	0.000008
91.	c.2807dup	p.Ala938Glyfs*113	frameshift	1	Pathogenic	0.000000
92.	c.1291G>A	p.D431N	missense	1	VUS	0.000028
93.	c.1789C>T	p.R597W	missense	1	VUS	0.000038
94.	c.256_258del	p.Ser86del	inframe	1	VUS	0.000000
95.	c.3206C>A	p.P1069H	missense	1	Likely Pathogenic	0.000000
96.	c.2718_2719dup	p.Glu907Glyfs*18	frameshift	1	Pathogenic	0.000000
97.	c.2371C>T	p.Q791X	nonsense	1	Pathogenic	0.000000
98.	c.2161_2168del	p.Thr721Profs*23	frameshift	1	Pathogenic	0.000000
99.	c.1376_1377del	p.Pro459Leufs*15	frameshift	1	Pathogenic	0.000000
100.	c.2381C>A	p.P794Q	missense	1	VUS	0.000000
101.	c.1569dup	p.His524Alafs*7	frameshift	1	Pathogenic	0.000000
102.	c.1224-1G>T		essential splice site	1	Pathogenic	0.000000
103.	c.3253G>T	p.E1085X	nonsense	1	Pathogenic	0.000000
104.	c.1021G>C	p.G341R	missense	1	VUS	0.000000
105.	c.844C>T	p.R282W	missense	1	Likely Pathogenic	0.000000
106.	c.811_817delTTCCGCC		frameshift	1	Pathogenic	0.000000
107.	c.506-1G>A		essential splice site	1	Pathogenic	0.000000
108.	c.932C>A	p.S311X	nonsense	1	Pathogenic	0.000000
109.	c.2198G>A	p.R733H	missense	1	VUS	0.000034
110.	c.1090+2T>C		essential splice site	1	Pathogenic	0.000000
111.	c.365C>A	p.A122D	missense	1	VUS	0.000000
112.	c.1999_2000delinsG	p.Leu667AspfsX15	frameshift	1	Pathogenic	0.000000
113.	c.701C>A	p.T234N	missense	1	Likely Pathogenic	0.000000
114.	c.3676C>T	p.R1226C	missense	1	VUS	0.000058
115.	c.1624+1G>A		essential splice site	1	Pathogenic	0.000000
116.	c.2249C>T	p.T750M	missense	1	Likely Pathogenic	0.000024
117.	c.2738-2A>G		essential splice site	1	Pathogenic	0.000000
118.	c.1213A>G	p.M405V	missense	1	VUS	0.000000
119.	c.211_212delinsTA	p.Val71*	frameshift	1	Pathogenic	0.000000
120.	c.2968C>G	p.P990A	missense	1	Likely Pathogenic	0.000000
121.	c.1377delC		frameshift	1	Pathogenic	0.000000
122.	c.2584C>T	p.Q862X	nonsense	1	Pathogenic	0.000000
123.	c.3316del	p.Asp1106Thrfs*83	frameshift	1	Pathogenic	0.000000
124.	c.2502del	p.Arg835Alafs*2	frameshift	1	Pathogenic	0.000000
125.	c.1756C>G	p.P586A	missense	1	Likely Pathogenic	0.000000
126.	c.2603-2_2603-1delinsGA		essential splice site	1	Pathogenic	0.000000
127.	c.1090+1G>A		essential splice site	1	Pathogenic	0.000000
128.	c.1405C>T	p.Q469X	nonsense	1	Pathogenic	0.000000
129.	c.1266_1267insTGAT	p.Ile423*	frameshift	1	Pathogenic	0.000000
130.	c.3614G>A	p.R1205Q	missense	1	VUS	0.000016
131.	c.1457G>A	p.W486X	nonsense	1	Pathogenic	0.000000
132.	c.3316G>A	p.D1106N	missense	1	VUS	0.000061
133.	c.3572C>T	p.S1191L	missense	1	VUS	0.000016
134.	c.1072G>A	p.D358N	missense	1	VUS	0.000008
135.	c.711C>A	p.Y237X	nonsense	1	Pathogenic	0.000000
136.	c.2304_2308+2delCATCGGT		essential splice site	1	Pathogenic	0.000000
137.	c.821+1G>A		essential splice site	1	Pathogenic	0.000043
138.	c.2504G>T	p.R835L	missense	1	Likely Pathogenic	0.000074
139.	c.982delG		frameshift	1	Pathogenic	0.000000
140.	c.373G>T	p.A125S	missense	1	VUS	0.000000
141.	c.2030C>T	p.P677L	missense	1	VUS	0.000000
142.	c.3728C>G	p.P1243R	missense	1	VUS	0.000000
143.	c.631G>A	p.D211N	missense	1	VUS	0.000009
144.	c.1120C>T	p.Q374X	nonsense	1	Pathogenic	0.000000
145.	c.49C>T	p.R17W	missense	1	VUS	0.000023
146.	c.255del	p.Ser86Profs*10	frameshift	1	Pathogenic	0.000000
147.	c.1456T>G	p.W486G	missense	1	VUS	0.000000
148.	c.553_562del	p.Lys185Trpfs*12	frameshift	1	Pathogenic	0.000000
149.	c.3334_3351del	p.Trp1112_Glu1117del	inframe	1	Likely Pathogenic	0.000000
150.	c.1021_1028del	p.Gly341*	frameshift	1	Pathogenic	0.000000
151.	c.2789del	p.Leu930Argfs*2	frameshift	1	Pathogenic	0.000000
152.	c.1112C>T	p.P371L	missense	1	VUS	0.000028
153.	c.121dup	p.Arg41Profs*8	frameshift	1	Pathogenic	0.000000
154.	c.2834G>A	p.R945Q	missense	1	VUS	0.000000
155.	c.1303C>T	p.Q435X	nonsense	1	Pathogenic	0.000000
156.	c.2512dup	p.Glu838Glyfs*46	frameshift	1	Pathogenic	0.000000
157.	c.2708G>A	p.G903D	missense	1	Likely Pathogenic	0.000000
158.	c.1523_1525delinsT	p.Gln508Leufs*22	frameshift	1	Pathogenic	0.000000
159.	c.2054_2067+11del	p.Lys685Argfs*3	frameshift	1	Pathogenic	0.000000
160.	c.1359del	p.Val454Cysfs*12	frameshift	1	Pathogenic	0.000000
161.	c.3624delC		frameshift	1	Pathogenic	0.000000
162.	c.1223+2T>C		essential splice site	1	Pathogenic	0.000000
163.	c.3605delG		frameshift	1	Pathogenic	0.000000
164.	c.2534_2538delGCGTC		frameshift	1	Pathogenic	0.000000
165.	c.3064C>T	p.R1022C	missense	1	VUS	0.000008
166.	c.1021G>A	p.G341S	missense	1	VUS	0.000025
167.	c.2909G>A	p.R970Q	missense	1	Likely Pathogenic	0.000032
168.	c.1201C>T	p.Q401X	nonsense	1	Pathogenic	0.000000
169.	c.146_148delTCA	p.Ile49del	inframe	1	VUS	0.000039
170.	c.799C>G	p.L267V	missense	1	VUS	0.000080
171.	c.1841A>G	p.Y614C	missense	1	VUS	0.000000
172.	c.2449C>T	p.R817W	missense	1	VUS	0.000000
173.	c.459delC		frameshift	1	Pathogenic	0.000000
174.	c.2197C>T	p.R733C	missense	1	Likely Pathogenic	0.000085
175.	c.2558delG		frameshift	1	Pathogenic	0.000000
176.	c.3364A>T	p.T1122S	missense	1	Likely Pathogenic	0.000000
177.	c.1080G>C	p.K360N	missense	1	VUS	0.000000
178.	c.3792_3793del	p.Cys1264*	frameshift	1	Likely Pathogenic	0.000000
179.	c.1790G>A	p.R597Q	missense	1	VUS	0.000000
180.	c.351_352del	p.Gly118Argfs*8	frameshift	1	Pathogenic	0.000000
181.	c.3256T>C	p.W1086R	missense	1	VUS	0.000000
182.	c.187C>T	p.R63W	missense	1	VUS	0.000077
183.	c.1471G>A	p.V491M	missense	1	VUS	0.000058
184.	c.655-2del		essential splice site	1	Pathogenic	0.000000
185.	c.3656T>C	p.L1219P	missense	1	VUS	0.000000
186.	c.391dup	p.Ala131Glyfs*22	frameshift	1	Pathogenic	0.000000
187.	c.3297dup	p.Tyr1100Valfs*49	frameshift	1	Pathogenic	0.000000
188.	c.2149_2737del	p.Leu717Alafs*11	frameshift	1	Pathogenic	0.000000
189.	c.1153G>A	p.V385M	missense	1	VUS	0.000010
190.	c.177dup	p.Glu60Argfs*53	frameshift	1	Pathogenic	0.000000
191.	c.2953A>G	p.K985E	missense	1	Pathogenic	0.000000
192.	c.1351+1G>A		essential splice site	1	Pathogenic	0.000000
193.	c.1404del	p.Gln469Serfs*19	frameshift	1	Pathogenic	0.000000
194.	c.1731G>C	p.W577C	missense	1	VUS	0.000000
195.	c.2188del	p.Thr730Profs*24	frameshift	1	Pathogenic	0.000000
196.	c.3452C>T	p.A1151V	missense	1	VUS	0.000078
197.	c.1231A>G	p.I411V	missense	1	VUS	0.000000
198.	c.3257G>A	p.W1086X	nonsense	1	Pathogenic	0.000021
199.	c.1455A>T	p.K485N	missense	1	VUS	0.000000
200.	c.1037G>A	p.R346H	missense	1	VUS	0.000000
201.	c.2953A>T	p.K985X	nonsense	1	Pathogenic	0.000000
202.	c.532G>A	p.V178M	missense	1	VUS	0.000020
203.	c.3811C>T	p.R1271X	nonsense	1	VUS	0.000025
204.	c.2873C>T	p.T958I	missense	1	VUS	0.000065
205.	c.2503C>T	p.R835C	missense	1	VUS	0.000024
206.	c.188G>A	p.R63Q	missense	1	VUS	0.000039
207.	c.731del	p.Lys244Argfs*56	frameshift	1	Pathogenic	0.000000
208.	c.3614G>C	p.R1205P	missense	1	Likely Pathogenic	0.000000
209.	c.1685C>T	p.A562V	missense	1	VUS	0.000008
210.	c.2265C>A	p.N755K	missense	1	Pathogenic	0.000000
211.	c.1097A>C	p.Q366P	missense	1	VUS	0.000000
212.	c.*26+2T>C		essential splice site	1	Likely Pathogenic	0.000000
213.	c.2748G>A	p.W916X	nonsense	1	Pathogenic	0.000000
214.	c.3739G>A	p.D1247N	missense	1	VUS	0.000000
215.	c.1273C>T	p.Q425X	nonsense	1	Pathogenic	0.000000
216.	c.241G>T	p.V81F	missense	1	VUS	0.000000
217.	c.3043dup	p.Ala1015Glyfs*36	frameshift	1	Pathogenic	0.000000
218.	c.1433C>T	p.S478L	missense	1	Likely Pathogenic	0.000017
219.	c.2603-1G>C		essential splice site	1	Pathogenic	0.000000
220.	c.3330+1G>C		essential splice site	1	Pathogenic	0.000000
221.	c.1A>T	p.Met1?	missense	1	Likely Pathogenic	0.000000
222.	c.821+2T>G		essential splice site	1	Pathogenic	0.000000
223.	c.1797del	p.His599Glnfs*3	frameshift	1	Pathogenic	0.000000
224.	c.2690_2696del	p.Gly897Glufs*25	frameshift	1	Pathogenic	0.000000
225.	c.1090+1G>T		essential splice site	1	Pathogenic	0.000000
226.	c.2247C>A	p.Y749X	nonsense	1	Pathogenic	0.000000
227.	c.2429_2503delins23	p.Arg810Profs*10	frameshift	1	Pathogenic	0.000000
228.	c.1458G>A	p.W486X	nonsense	1	Pathogenic	0.000000
229.	c.3490+1G>A		essential splice site	1	Pathogenic	0.000000
230.	c.2065C>T	p.Q689X	nonsense	1	Pathogenic	0.000000
231.	c.1352_1353del	p.Glu451Alafs*23	frameshift	1	Pathogenic	0.000000
232.	c.3617delG		frameshift	1	Pathogenic	0.000000
233.	c.2995-1G>A		essential splice site	1	Pathogenic	0.000000
234.	c.3373G>A	p.V1125M	missense	1	VUS	0.000022

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.