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

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.