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.2459G>A	p.R820Q	missense	5	VUS	0.000016
24.	c.2308G>A	p.D770N	missense	5	Likely Pathogenic	0.000008
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.3763G>A	p.A1255T	missense	3	VUS	0.000075
36.	c.1720C>T	p.R574W	missense	3	VUS	0.000054
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.3600_3609delCTGCTGTGCT		frameshift	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.747C>A	p.C249X	nonsense	2	Pathogenic	0.000000
51.	c.1828G>A	p.D610N	missense	2	VUS	0.000000
52.	c.2432A>G	p.K811R	missense	2	VUS	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.2524dup	p.Tyr842Leufs*42	frameshift	2	Pathogenic	0.000000
58.	c.2905+2dup		essential splice site	2	Likely Pathogenic	0.000000
59.	c.2300A>G	p.K767R	missense	2	VUS	0.000016
60.	c.1483C>T	p.R495W	missense	2	Likely Pathogenic	0.000000
61.	c.3271del	p.Asp1091Metfs*98	frameshift	2	Pathogenic	0.000000
62.	c.177_187del	p.Glu60AlafsX49	frameshift	2	Pathogenic	0.000000
63.	c.3455_3466del	p.Ala1152_Lys1155del	inframe	2	Likely Pathogenic	0.000000
64.	c.557C>T	p.P186L	missense	2	VUS	0.000047
65.	c.3627+1G>T		essential splice site	2	Pathogenic	0.000000
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.3582_3593delGGGCTACACTGC		inframe	2	Likely Pathogenic	0.000000
69.	c.3751T>C	p.Y1251H	missense	2	VUS	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.1090+1G>A		essential splice site	1	Pathogenic	0.000000
77.	c.532G>A	p.V178M	missense	1	VUS	0.000020
78.	c.3614G>A	p.R1205Q	missense	1	VUS	0.000016
79.	c.188G>A	p.R63Q	missense	1	VUS	0.000039
80.	c.3614G>C	p.R1205P	missense	1	Likely Pathogenic	0.000000
81.	c.*26+2T>C		essential splice site	1	Likely Pathogenic	0.000000
82.	c.3043dup	p.Ala1015Glyfs*36	frameshift	1	Pathogenic	0.000000
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.2690_2696del	p.Gly897Glufs*25	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.3656T>C	p.L1219P	missense	1	VUS	0.000000
95.	c.1797del	p.His599Glnfs*3	frameshift	1	Pathogenic	0.000000
96.	c.2030C>T	p.P677L	missense	1	VUS	0.000000
97.	c.1458G>A	p.W486X	nonsense	1	Pathogenic	0.000000
98.	c.1120C>T	p.Q374X	nonsense	1	Pathogenic	0.000000
99.	c.2065C>T	p.Q689X	nonsense	1	Pathogenic	0.000000
100.	c.1352_1353del	p.Glu451Alafs*23	frameshift	1	Pathogenic	0.000000
101.	c.1456T>G	p.W486G	missense	1	VUS	0.000000
102.	c.553_562del	p.Lys185Trpfs*12	frameshift	1	Pathogenic	0.000000
103.	c.1021_1028del	p.Gly341*	frameshift	1	Pathogenic	0.000000
104.	c.255del	p.Ser86Profs*10	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.3357C>A	p.Y1119X	nonsense	1	Pathogenic	0.000000
114.	c.3811C>T	p.R1271X	nonsense	1	VUS	0.000025
115.	c.2807dup	p.Ala938Glyfs*113	frameshift	1	Pathogenic	0.000000
116.	c.3206C>A	p.P1069H	missense	1	Likely Pathogenic	0.000000
117.	c.3605delG		frameshift	1	Pathogenic	0.000000
118.	c.2534_2538delGCGTC		frameshift	1	Pathogenic	0.000000
119.	c.3064C>T	p.R1022C	missense	1	VUS	0.000008
120.	c.2718_2719dup	p.Glu907Glyfs*18	frameshift	1	Pathogenic	0.000000
121.	c.2371C>T	p.Q791X	nonsense	1	Pathogenic	0.000000
122.	c.2909G>A	p.R970Q	missense	1	Likely Pathogenic	0.000032
123.	c.1841A>G	p.Y614C	missense	1	VUS	0.000000
124.	c.1376_1377del	p.Pro459Leufs*15	frameshift	1	Pathogenic	0.000000
125.	c.2449C>T	p.R817W	missense	1	VUS	0.000000
126.	c.2381C>A	p.P794Q	missense	1	VUS	0.000000
127.	c.2197C>T	p.R733C	missense	1	Likely Pathogenic	0.000085
128.	c.1569dup	p.His524Alafs*7	frameshift	1	Pathogenic	0.000000
129.	c.2558delG		frameshift	1	Pathogenic	0.000000
130.	c.1201C>T	p.Q401X	nonsense	1	Pathogenic	0.000000
131.	c.2161_2168del	p.Thr721Profs*23	frameshift	1	Pathogenic	0.000000
132.	c.1080G>C	p.K360N	missense	1	VUS	0.000000
133.	c.351_352del	p.Gly118Argfs*8	frameshift	1	Pathogenic	0.000000
134.	c.1790G>A	p.R597Q	missense	1	VUS	0.000000
135.	c.1224-1G>T		essential splice site	1	Pathogenic	0.000000
136.	c.1471G>A	p.V491M	missense	1	VUS	0.000058
137.	c.655-2del		essential splice site	1	Pathogenic	0.000000
138.	c.1021G>C	p.G341R	missense	1	VUS	0.000000
139.	c.1153G>A	p.V385M	missense	1	VUS	0.000010
140.	c.177dup	p.Glu60Argfs*53	frameshift	1	Pathogenic	0.000000
141.	c.844C>T	p.R282W	missense	1	Likely Pathogenic	0.000000
142.	c.1351+1G>A		essential splice site	1	Pathogenic	0.000000
143.	c.391dup	p.Ala131Glyfs*22	frameshift	1	Pathogenic	0.000000
144.	c.506-1G>A		essential splice site	1	Pathogenic	0.000000
145.	c.932C>A	p.S311X	nonsense	1	Pathogenic	0.000000
146.	c.811_817delTTCCGCC		frameshift	1	Pathogenic	0.000000
147.	c.3257G>A	p.W1086X	nonsense	1	Pathogenic	0.000021
148.	c.3452C>T	p.A1151V	missense	1	VUS	0.000078
149.	c.2738-2A>G		essential splice site	1	Pathogenic	0.000000
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.3713T>C	p.L1238P	missense	1	Likely Pathogenic	0.000000
155.	c.1756C>G	p.P586A	missense	1	Likely Pathogenic	0.000000
156.	c.2603-2_2603-1delinsGA		essential splice site	1	Pathogenic	0.000000
157.	c.2873C>T	p.T958I	missense	1	VUS	0.000065
158.	c.1405C>T	p.Q469X	nonsense	1	Pathogenic	0.000000
159.	c.2503C>T	p.R835C	missense	1	VUS	0.000024
160.	c.2502del	p.Arg835Alafs*2	frameshift	1	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.1273C>T	p.Q425X	nonsense	1	Pathogenic	0.000000
168.	c.241G>T	p.V81F	missense	1	VUS	0.000000
169.	c.1433C>T	p.S478L	missense	1	Likely Pathogenic	0.000017
170.	c.1072G>A	p.D358N	missense	1	VUS	0.000008
171.	c.1A>T	p.Met1?	missense	1	Likely Pathogenic	0.000000
172.	c.821+2T>G		essential splice site	1	Pathogenic	0.000000
173.	c.711C>A	p.Y237X	nonsense	1	Pathogenic	0.000000
174.	c.1090+1G>T		essential splice site	1	Pathogenic	0.000000
175.	c.821+1G>A		essential splice site	1	Pathogenic	0.000043
176.	c.982delG		frameshift	1	Pathogenic	0.000000
177.	c.3728C>G	p.P1243R	missense	1	VUS	0.000000
178.	c.631G>A	p.D211N	missense	1	VUS	0.000009
179.	c.3490+1G>A		essential splice site	1	Pathogenic	0.000000
180.	c.49C>T	p.R17W	missense	1	VUS	0.000023
181.	c.3617delG		frameshift	1	Pathogenic	0.000000
182.	c.373G>T	p.A125S	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.2834G>A	p.R945Q	missense	1	VUS	0.000000
188.	c.2512dup	p.Glu838Glyfs*46	frameshift	1	Pathogenic	0.000000
189.	c.3019T>C	p.W1007R	missense	1	VUS	0.000000
190.	c.3676C>T	p.R1226C	missense	1	VUS	0.000058
191.	c.2708G>A	p.G903D	missense	1	Likely Pathogenic	0.000000
192.	c.1174G>T	p.A392S	missense	1	VUS	0.000000
193.	c.2269G>A	p.V757M	missense	1	VUS	0.000066
194.	c.2054_2067+11del	p.Lys685Argfs*3	frameshift	1	Pathogenic	0.000000
195.	c.1828G>C	p.D610H	missense	1	VUS	0.000058
196.	c.1359del	p.Val454Cysfs*12	frameshift	1	Pathogenic	0.000000
197.	c.1523_1525delinsT	p.Gln508Leufs*22	frameshift	1	Pathogenic	0.000000
198.	c.100_110dup	p.Val38Serfs*5	frameshift	1	Pathogenic	0.000000
199.	c.1591G>A	p.G531R	missense	1	Likely Pathogenic	0.000017
200.	c.1038_1042dupCGGCA		frameshift	1	Pathogenic	0.000008
201.	c.1291G>A	p.D431N	missense	1	VUS	0.000028
202.	c.256_258del	p.Ser86del	inframe	1	VUS	0.000000
203.	c.1789C>T	p.R597W	missense	1	VUS	0.000038
204.	c.1223+2T>C		essential splice site	1	Pathogenic	0.000000
205.	c.611_618delinsT	p.Gly204Valfs*94	frameshift	1	Pathogenic	0.000000
206.	c.1898-1G>A		essential splice site	1	Pathogenic	0.000000
207.	c.1021G>A	p.G341S	missense	1	VUS	0.000025
208.	c.146_148delTCA	p.Ile49del	inframe	1	VUS	0.000039
209.	c.799C>G	p.L267V	missense	1	VUS	0.000080
210.	c.459delC		frameshift	1	Pathogenic	0.000000
211.	c.3792_3793del	p.Cys1264*	frameshift	1	Likely Pathogenic	0.000000
212.	c.3256T>C	p.W1086R	missense	1	VUS	0.000000
213.	c.187C>T	p.R63W	missense	1	VUS	0.000077
214.	c.3253G>T	p.E1085X	nonsense	1	Pathogenic	0.000000
215.	c.3364A>T	p.T1122S	missense	1	Likely Pathogenic	0.000000
216.	c.3297dup	p.Tyr1100Valfs*49	frameshift	1	Pathogenic	0.000000
217.	c.2149_2737del	p.Leu717Alafs*11	frameshift	1	Pathogenic	0.000000
218.	c.2953A>G	p.K985E	missense	1	Pathogenic	0.000000
219.	c.1404del	p.Gln469Serfs*19	frameshift	1	Pathogenic	0.000000
220.	c.2198G>A	p.R733H	missense	1	VUS	0.000034
221.	c.1731G>C	p.W577C	missense	1	VUS	0.000000
222.	c.2188del	p.Thr730Profs*24	frameshift	1	Pathogenic	0.000000
223.	c.365C>A	p.A122D	missense	1	VUS	0.000000
224.	c.1231A>G	p.I411V	missense	1	VUS	0.000000
225.	c.701C>A	p.T234N	missense	1	Likely Pathogenic	0.000000
226.	c.1999_2000delinsG	p.Leu667AspfsX15	frameshift	1	Pathogenic	0.000000
227.	c.1455A>T	p.K485N	missense	1	VUS	0.000000
228.	c.1624+1G>A		essential splice site	1	Pathogenic	0.000000
229.	c.1090+2T>C		essential splice site	1	Pathogenic	0.000000
230.	c.2249C>T	p.T750M	missense	1	Likely Pathogenic	0.000024
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.