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