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.2604_2605delinsA	p.S871fs	frameshift	8	Pathogenic	0.000000
15.	c.927-2A>G		essential splice site	8	Pathogenic	0.000000
16.	c.2864_2865delCT		frameshift	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.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.484C>T	p.Q162X	nonsense	4	Pathogenic	0.000000
26.	c.3697C>T	p.Q1233X	nonsense	4	Likely Pathogenic	0.000008
27.	c.2556_2557delinsTCT	p.Gly853fs	frameshift	4	Pathogenic	0.000000
28.	c.1484G>A	p.R495Q	missense	4	Likely Pathogenic	0.000008
29.	c.821+2T>C		essential splice site	4	Pathogenic	0.000000
30.	c.442G>A	p.G148R	missense	4	Likely Pathogenic	0.000042
31.	c.3798C>G	p.C1266W	missense	4	VUS	0.000000
32.	c.3163A>T	p.K1055X	nonsense	4	Pathogenic	0.000000
33.	c.2210C>T	p.T737M	missense	3	VUS	0.000050
34.	c.3129C>A	p.Y1043X	nonsense	3	Pathogenic	0.000000
35.	c.2309-1G>A		essential splice site	3	Pathogenic	0.000000
36.	c.2905+1G>A		essential splice site	3	Pathogenic	0.000000
37.	c.1123G>A	p.V375M	missense	3	VUS	0.000009
38.	c.3763G>A	p.A1255T	missense	3	VUS	0.000075
39.	c.3408C>A	p.Y1136X	nonsense	3	Pathogenic	0.000000
40.	c.3600_3609delCTGCTGTGCT		frameshift	3	Pathogenic	0.000000
41.	c.2545del	p.Val849Serfs*30	frameshift	3	Pathogenic	0.000000
42.	c.3277G>T	p.G1093C	missense	3	VUS	0.000020
43.	c.710A>C	p.Y237S	missense	3	Likely Pathogenic	0.000000
44.	c.3181C>T	p.Q1061X	nonsense	3	Pathogenic	0.000016
45.	c.1720C>T	p.R574W	missense	3	VUS	0.000054
46.	c.3286G>T	p.E1096X	nonsense	3	Pathogenic	0.000000
47.	c.2308+1G>A		essential splice site	2	Pathogenic	0.000000
48.	c.2219G>C	p.G740A	missense	2	VUS	0.000000
49.	c.3751T>C	p.Y1251H	missense	2	VUS	0.000000
50.	c.3582_3593delGGGCTACACTGC		inframe	2	Likely Pathogenic	0.000000
51.	c.1886T>C	p.L629P	missense	2	VUS	0.000000
52.	c.2526C>G	p.Y842X	nonsense	2	Pathogenic	0.000000
53.	c.126G>A	p.W42X	nonsense	2	Pathogenic	0.000000
54.	c.833delG	p.Gly278GlufsX22	frameshift	2	Pathogenic	0.000000
55.	c.2573G>A	p.S858N	missense	2	Likely Pathogenic	0.000000
56.	c.443dup	p.Ala149Serfs*4	frameshift	2	Pathogenic	0.000000
57.	c.818G>A	p.R273H	missense	2	VUS	0.000042
58.	c.3470C>T	p.P1157L	missense	2	VUS	0.000093
59.	c.2905C>T	p.Q969X	nonsense	2	Pathogenic	0.000000
60.	c.1828G>A	p.D610N	missense	2	VUS	0.000000
61.	c.2432A>G	p.K811R	missense	2	VUS	0.000000
62.	c.747C>A	p.C249X	nonsense	2	Pathogenic	0.000000
63.	c.25+1G>A		essential splice site	2	Pathogenic	0.000000
64.	c.1505G>A	p.R502Q	missense	2	Pathogenic	0.000000
65.	c.3005G>A	p.R1002Q	missense	2	VUS	0.000046
66.	c.3627+1G>T		essential splice site	2	Pathogenic	0.000000
67.	c.3752A>G	p.Y1251C	missense	2	VUS	0.000000
68.	c.2905+2dup		essential splice site	2	Likely Pathogenic	0.000000
69.	c.2524dup	p.Tyr842Leufs*42	frameshift	2	Pathogenic	0.000000
70.	c.2300A>G	p.K767R	missense	2	VUS	0.000016
71.	c.1483C>T	p.R495W	missense	2	Likely Pathogenic	0.000000
72.	c.3455_3466del	p.Ala1152_Lys1155del	inframe	2	Likely Pathogenic	0.000000
73.	c.557C>T	p.P186L	missense	2	VUS	0.000047
74.	c.3271del	p.Asp1091Metfs*98	frameshift	2	Pathogenic	0.000000
75.	c.177_187del	p.Glu60AlafsX49	frameshift	2	Pathogenic	0.000000
76.	c.1405C>T	p.Q469X	nonsense	1	Pathogenic	0.000000
77.	c.2503C>T	p.R835C	missense	1	VUS	0.000024
78.	c.2502del	p.Arg835Alafs*2	frameshift	1	Pathogenic	0.000000
79.	c.1756C>G	p.P586A	missense	1	Likely Pathogenic	0.000000
80.	c.2603-2_2603-1delinsGA		essential splice site	1	Pathogenic	0.000000
81.	c.2873C>T	p.T958I	missense	1	VUS	0.000065
82.	c.1097A>C	p.Q366P	missense	1	VUS	0.000000
83.	c.2265C>A	p.N755K	missense	1	Pathogenic	0.000000
84.	c.1266_1267insTGAT	p.Ile423*	frameshift	1	Pathogenic	0.000000
85.	c.731del	p.Lys244Argfs*56	frameshift	1	Pathogenic	0.000000
86.	c.1457G>A	p.W486X	nonsense	1	Pathogenic	0.000000
87.	c.1685C>T	p.A562V	missense	1	VUS	0.000008
88.	c.1072G>A	p.D358N	missense	1	VUS	0.000008
89.	c.1A>T	p.Met1?	missense	1	Likely Pathogenic	0.000000
90.	c.821+2T>G		essential splice site	1	Pathogenic	0.000000
91.	c.1273C>T	p.Q425X	nonsense	1	Pathogenic	0.000000
92.	c.241G>T	p.V81F	missense	1	VUS	0.000000
93.	c.1433C>T	p.S478L	missense	1	Likely Pathogenic	0.000017
94.	c.982delG		frameshift	1	Pathogenic	0.000000
95.	c.711C>A	p.Y237X	nonsense	1	Pathogenic	0.000000
96.	c.1090+1G>T		essential splice site	1	Pathogenic	0.000000
97.	c.821+1G>A		essential splice site	1	Pathogenic	0.000043
98.	c.3617delG		frameshift	1	Pathogenic	0.000000
99.	c.373G>T	p.A125S	missense	1	VUS	0.000000
100.	c.3728C>G	p.P1243R	missense	1	VUS	0.000000
101.	c.631G>A	p.D211N	missense	1	VUS	0.000009
102.	c.3490+1G>A		essential splice site	1	Pathogenic	0.000000
103.	c.49C>T	p.R17W	missense	1	VUS	0.000023
104.	c.2789del	p.Leu930Argfs*2	frameshift	1	Pathogenic	0.000000
105.	c.3373G>A	p.V1125M	missense	1	VUS	0.000022
106.	c.2995-1G>A		essential splice site	1	Pathogenic	0.000000
107.	c.3334_3351del	p.Trp1112_Glu1117del	inframe	1	Likely Pathogenic	0.000000
108.	c.2708G>A	p.G903D	missense	1	Likely Pathogenic	0.000000
109.	c.2834G>A	p.R945Q	missense	1	VUS	0.000000
110.	c.2512dup	p.Glu838Glyfs*46	frameshift	1	Pathogenic	0.000000
111.	c.3019T>C	p.W1007R	missense	1	VUS	0.000000
112.	c.1523_1525delinsT	p.Gln508Leufs*22	frameshift	1	Pathogenic	0.000000
113.	c.1174G>T	p.A392S	missense	1	VUS	0.000000
114.	c.2269G>A	p.V757M	missense	1	VUS	0.000066
115.	c.2054_2067+11del	p.Lys685Argfs*3	frameshift	1	Pathogenic	0.000000
116.	c.1828G>C	p.D610H	missense	1	VUS	0.000058
117.	c.1359del	p.Val454Cysfs*12	frameshift	1	Pathogenic	0.000000
118.	c.256_258del	p.Ser86del	inframe	1	VUS	0.000000
119.	c.1789C>T	p.R597W	missense	1	VUS	0.000038
120.	c.1223+2T>C		essential splice site	1	Pathogenic	0.000000
121.	c.611_618delinsT	p.Gly204Valfs*94	frameshift	1	Pathogenic	0.000000
122.	c.1898-1G>A		essential splice site	1	Pathogenic	0.000000
123.	c.100_110dup	p.Val38Serfs*5	frameshift	1	Pathogenic	0.000000
124.	c.1591G>A	p.G531R	missense	1	Likely Pathogenic	0.000017
125.	c.1038_1042dupCGGCA		frameshift	1	Pathogenic	0.000008
126.	c.1291G>A	p.D431N	missense	1	VUS	0.000028
127.	c.1021G>A	p.G341S	missense	1	VUS	0.000025
128.	c.146_148delTCA	p.Ile49del	inframe	1	VUS	0.000039
129.	c.799C>G	p.L267V	missense	1	VUS	0.000080
130.	c.459delC		frameshift	1	Pathogenic	0.000000
131.	c.187C>T	p.R63W	missense	1	VUS	0.000077
132.	c.3253G>T	p.E1085X	nonsense	1	Pathogenic	0.000000
133.	c.3364A>T	p.T1122S	missense	1	Likely Pathogenic	0.000000
134.	c.3656T>C	p.L1219P	missense	1	VUS	0.000000
135.	c.3792_3793del	p.Cys1264*	frameshift	1	Likely Pathogenic	0.000000
136.	c.3256T>C	p.W1086R	missense	1	VUS	0.000000
137.	c.2953A>G	p.K985E	missense	1	Pathogenic	0.000000
138.	c.3297dup	p.Tyr1100Valfs*49	frameshift	1	Pathogenic	0.000000
139.	c.2149_2737del	p.Leu717Alafs*11	frameshift	1	Pathogenic	0.000000
140.	c.2188del	p.Thr730Profs*24	frameshift	1	Pathogenic	0.000000
141.	c.1404del	p.Gln469Serfs*19	frameshift	1	Pathogenic	0.000000
142.	c.2198G>A	p.R733H	missense	1	VUS	0.000034
143.	c.1731G>C	p.W577C	missense	1	VUS	0.000000
144.	c.1624+1G>A		essential splice site	1	Pathogenic	0.000000
145.	c.1090+2T>C		essential splice site	1	Pathogenic	0.000000
146.	c.2249C>T	p.T750M	missense	1	Likely Pathogenic	0.000024
147.	c.365C>A	p.A122D	missense	1	VUS	0.000000
148.	c.1231A>G	p.I411V	missense	1	VUS	0.000000
149.	c.701C>A	p.T234N	missense	1	Likely Pathogenic	0.000000
150.	c.1999_2000delinsG	p.Leu667AspfsX15	frameshift	1	Pathogenic	0.000000
151.	c.1455A>T	p.K485N	missense	1	VUS	0.000000
152.	c.1377delC		frameshift	1	Pathogenic	0.000000
153.	c.1037G>A	p.R346H	missense	1	VUS	0.000000
154.	c.1213A>G	p.M405V	missense	1	VUS	0.000000
155.	c.211_212delinsTA	p.Val71*	frameshift	1	Pathogenic	0.000000
156.	c.532G>A	p.V178M	missense	1	VUS	0.000020
157.	c.3811C>T	p.R1271X	nonsense	1	VUS	0.000025
158.	c.1090+1G>A		essential splice site	1	Pathogenic	0.000000
159.	c.*26+2T>C		essential splice site	1	Likely Pathogenic	0.000000
160.	c.3614G>A	p.R1205Q	missense	1	VUS	0.000016
161.	c.188G>A	p.R63Q	missense	1	VUS	0.000039
162.	c.3614G>C	p.R1205P	missense	1	Likely Pathogenic	0.000000
163.	c.2748G>A	p.W916X	nonsense	1	Pathogenic	0.000000
164.	c.3316G>A	p.D1106N	missense	1	VUS	0.000061
165.	c.3739G>A	p.D1247N	missense	1	VUS	0.000000
166.	c.3043dup	p.Ala1015Glyfs*36	frameshift	1	Pathogenic	0.000000
167.	c.3572C>T	p.S1191L	missense	1	VUS	0.000016
168.	c.2603-1G>C		essential splice site	1	Pathogenic	0.000000
169.	c.3330+1G>C		essential splice site	1	Pathogenic	0.000000
170.	c.2504G>T	p.R835L	missense	1	Likely Pathogenic	0.000074
171.	c.2429_2503delins23	p.Arg810Profs*10	frameshift	1	Pathogenic	0.000000
172.	c.1797del	p.His599Glnfs*3	frameshift	1	Pathogenic	0.000000
173.	c.2690_2696del	p.Gly897Glufs*25	frameshift	1	Pathogenic	0.000000
174.	c.2304_2308+2delCATCGGT		essential splice site	1	Pathogenic	0.000000
175.	c.2247C>A	p.Y749X	nonsense	1	Pathogenic	0.000000
176.	c.1352_1353del	p.Glu451Alafs*23	frameshift	1	Pathogenic	0.000000
177.	c.2030C>T	p.P677L	missense	1	VUS	0.000000
178.	c.1458G>A	p.W486X	nonsense	1	Pathogenic	0.000000
179.	c.1120C>T	p.Q374X	nonsense	1	Pathogenic	0.000000
180.	c.2065C>T	p.Q689X	nonsense	1	Pathogenic	0.000000
181.	c.255del	p.Ser86Profs*10	frameshift	1	Pathogenic	0.000000
182.	c.1456T>G	p.W486G	missense	1	VUS	0.000000
183.	c.553_562del	p.Lys185Trpfs*12	frameshift	1	Pathogenic	0.000000
184.	c.1021_1028del	p.Gly341*	frameshift	1	Pathogenic	0.000000
185.	c.994G>A	p.E332K	missense	1	VUS	0.000009
186.	c.743_746delACTG		frameshift	1	Pathogenic	0.000000
187.	c.1112C>T	p.P371L	missense	1	VUS	0.000028
188.	c.121dup	p.Arg41Profs*8	frameshift	1	Pathogenic	0.000000
189.	c.1303C>T	p.Q435X	nonsense	1	Pathogenic	0.000000
190.	c.3624delC		frameshift	1	Pathogenic	0.000000
191.	c.3713T>C	p.L1238P	missense	1	Likely Pathogenic	0.000000
192.	c.148A>G	p.S50G	missense	1	VUS	0.000038
193.	c.772+1G>A		essential splice site	1	Pathogenic	0.000000
194.	c.3206C>A	p.P1069H	missense	1	Likely Pathogenic	0.000000
195.	c.3605delG		frameshift	1	Pathogenic	0.000000
196.	c.3357C>A	p.Y1119X	nonsense	1	Pathogenic	0.000000
197.	c.2807dup	p.Ala938Glyfs*113	frameshift	1	Pathogenic	0.000000
198.	c.2371C>T	p.Q791X	nonsense	1	Pathogenic	0.000000
199.	c.2909G>A	p.R970Q	missense	1	Likely Pathogenic	0.000032
200.	c.2534_2538delGCGTC		frameshift	1	Pathogenic	0.000000
201.	c.3064C>T	p.R1022C	missense	1	VUS	0.000008
202.	c.2718_2719dup	p.Glu907Glyfs*18	frameshift	1	Pathogenic	0.000000
203.	c.2197C>T	p.R733C	missense	1	Likely Pathogenic	0.000085
204.	c.1569dup	p.His524Alafs*7	frameshift	1	Pathogenic	0.000000
205.	c.2558delG		frameshift	1	Pathogenic	0.000000
206.	c.1201C>T	p.Q401X	nonsense	1	Pathogenic	0.000000
207.	c.2161_2168del	p.Thr721Profs*23	frameshift	1	Pathogenic	0.000000
208.	c.1841A>G	p.Y614C	missense	1	VUS	0.000000
209.	c.1376_1377del	p.Pro459Leufs*15	frameshift	1	Pathogenic	0.000000
210.	c.2449C>T	p.R817W	missense	1	VUS	0.000000
211.	c.2381C>A	p.P794Q	missense	1	VUS	0.000000
212.	c.1471G>A	p.V491M	missense	1	VUS	0.000058
213.	c.655-2del		essential splice site	1	Pathogenic	0.000000
214.	c.1080G>C	p.K360N	missense	1	VUS	0.000000
215.	c.351_352del	p.Gly118Argfs*8	frameshift	1	Pathogenic	0.000000
216.	c.1790G>A	p.R597Q	missense	1	VUS	0.000000
217.	c.1224-1G>T		essential splice site	1	Pathogenic	0.000000
218.	c.844C>T	p.R282W	missense	1	Likely Pathogenic	0.000000
219.	c.1351+1G>A		essential splice site	1	Pathogenic	0.000000
220.	c.391dup	p.Ala131Glyfs*22	frameshift	1	Pathogenic	0.000000
221.	c.1021G>C	p.G341R	missense	1	VUS	0.000000
222.	c.1153G>A	p.V385M	missense	1	VUS	0.000010
223.	c.177dup	p.Glu60Argfs*53	frameshift	1	Pathogenic	0.000000
224.	c.811_817delTTCCGCC		frameshift	1	Pathogenic	0.000000
225.	c.506-1G>A		essential splice site	1	Pathogenic	0.000000
226.	c.932C>A	p.S311X	nonsense	1	Pathogenic	0.000000
227.	c.3257G>A	p.W1086X	nonsense	1	Pathogenic	0.000021
228.	c.3676C>T	p.R1226C	missense	1	VUS	0.000058
229.	c.3452C>T	p.A1151V	missense	1	VUS	0.000078
230.	c.2584C>T	p.Q862X	nonsense	1	Pathogenic	0.000000
231.	c.3316del	p.Asp1106Thrfs*83	frameshift	1	Pathogenic	0.000000
232.	c.2738-2A>G		essential splice site	1	Pathogenic	0.000000
233.	c.2953A>T	p.K985X	nonsense	1	Pathogenic	0.000000
234.	c.2968C>G	p.P990A	missense	1	Likely 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.