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