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.3613C>T	p.R1205W	missense	10	Likely Pathogenic	0.000016
11.	c.1483C>G	p.R495G	missense	10	Likely Pathogenic	0.000000
12.	c.1928-2A>G		essential splice site	10	Pathogenic	0.000000
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.2864_2865delCT		frameshift	8	Pathogenic	0.000000
16.	c.927-2A>G		essential splice site	8	Pathogenic	0.000000
17.	c.2490_2491insT	p.His831SerfsTer2	frameshift	7	Pathogenic	0.000024
18.	c.3190+2T>G		essential splice site	7	Pathogenic	0.000016
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.3163A>T	p.K1055X	nonsense	4	Pathogenic	0.000000
26.	c.484C>T	p.Q162X	nonsense	4	Pathogenic	0.000000
27.	c.821+2T>C		essential splice site	4	Pathogenic	0.000000
28.	c.442G>A	p.G148R	missense	4	Likely Pathogenic	0.000042
29.	c.2556_2557delinsTCT	p.Gly853fs	frameshift	4	Pathogenic	0.000000
30.	c.3798C>G	p.C1266W	missense	4	VUS	0.000000
31.	c.1484G>A	p.R495Q	missense	4	Likely Pathogenic	0.000008
32.	c.3697C>T	p.Q1233X	nonsense	4	Likely Pathogenic	0.000008
33.	c.2545del	p.Val849Serfs*30	frameshift	3	Pathogenic	0.000000
34.	c.3286G>T	p.E1096X	nonsense	3	Pathogenic	0.000000
35.	c.710A>C	p.Y237S	missense	3	Likely Pathogenic	0.000000
36.	c.2210C>T	p.T737M	missense	3	VUS	0.000050
37.	c.2905+1G>A		essential splice site	3	Pathogenic	0.000000
38.	c.1123G>A	p.V375M	missense	3	VUS	0.000009
39.	c.3600_3609delCTGCTGTGCT		frameshift	3	Pathogenic	0.000000
40.	c.3408C>A	p.Y1136X	nonsense	3	Pathogenic	0.000000
41.	c.3277G>T	p.G1093C	missense	3	VUS	0.000020
42.	c.3181C>T	p.Q1061X	nonsense	3	Pathogenic	0.000016
43.	c.1720C>T	p.R574W	missense	3	VUS	0.000054
44.	c.3129C>A	p.Y1043X	nonsense	3	Pathogenic	0.000000
45.	c.2309-1G>A		essential splice site	3	Pathogenic	0.000000
46.	c.3763G>A	p.A1255T	missense	3	VUS	0.000075
47.	c.1483C>T	p.R495W	missense	2	Likely Pathogenic	0.000000
48.	c.2308+1G>A		essential splice site	2	Pathogenic	0.000000
49.	c.818G>A	p.R273H	missense	2	VUS	0.000042
50.	c.3582_3593delGGGCTACACTGC		inframe	2	Likely Pathogenic	0.000000
51.	c.2526C>G	p.Y842X	nonsense	2	Pathogenic	0.000000
52.	c.3752A>G	p.Y1251C	missense	2	VUS	0.000000
53.	c.3627+1G>T		essential splice site	2	Pathogenic	0.000000
54.	c.126G>A	p.W42X	nonsense	2	Pathogenic	0.000000
55.	c.2905+2dup		essential splice site	2	Likely Pathogenic	0.000000
56.	c.2524dup	p.Tyr842Leufs*42	frameshift	2	Pathogenic	0.000000
57.	c.2573G>A	p.S858N	missense	2	Likely Pathogenic	0.000000
58.	c.177_187del	p.Glu60AlafsX49	frameshift	2	Pathogenic	0.000000
59.	c.3455_3466del	p.Ala1152_Lys1155del	inframe	2	Likely Pathogenic	0.000000
60.	c.557C>T	p.P186L	missense	2	VUS	0.000047
61.	c.3271del	p.Asp1091Metfs*98	frameshift	2	Pathogenic	0.000000
62.	c.443dup	p.Ala149Serfs*4	frameshift	2	Pathogenic	0.000000
63.	c.2219G>C	p.G740A	missense	2	VUS	0.000000
64.	c.3470C>T	p.P1157L	missense	2	VUS	0.000093
65.	c.2905C>T	p.Q969X	nonsense	2	Pathogenic	0.000000
66.	c.1828G>A	p.D610N	missense	2	VUS	0.000000
67.	c.2432A>G	p.K811R	missense	2	VUS	0.000000
68.	c.747C>A	p.C249X	nonsense	2	Pathogenic	0.000000
69.	c.1505G>A	p.R502Q	missense	2	Pathogenic	0.000000
70.	c.25+1G>A		essential splice site	2	Pathogenic	0.000000
71.	c.3751T>C	p.Y1251H	missense	2	VUS	0.000000
72.	c.1886T>C	p.L629P	missense	2	VUS	0.000000
73.	c.3005G>A	p.R1002Q	missense	2	VUS	0.000046
74.	c.833delG	p.Gly278GlufsX22	frameshift	2	Pathogenic	0.000000
75.	c.2300A>G	p.K767R	missense	2	VUS	0.000016
76.	c.1153G>A	p.V385M	missense	1	VUS	0.000010
77.	c.177dup	p.Glu60Argfs*53	frameshift	1	Pathogenic	0.000000
78.	c.2953A>G	p.K985E	missense	1	Pathogenic	0.000000
79.	c.1351+1G>A		essential splice site	1	Pathogenic	0.000000
80.	c.391dup	p.Ala131Glyfs*22	frameshift	1	Pathogenic	0.000000
81.	c.3297dup	p.Tyr1100Valfs*49	frameshift	1	Pathogenic	0.000000
82.	c.2149_2737del	p.Leu717Alafs*11	frameshift	1	Pathogenic	0.000000
83.	c.1731G>C	p.W577C	missense	1	VUS	0.000000
84.	c.2188del	p.Thr730Profs*24	frameshift	1	Pathogenic	0.000000
85.	c.1404del	p.Gln469Serfs*19	frameshift	1	Pathogenic	0.000000
86.	c.3257G>A	p.W1086X	nonsense	1	Pathogenic	0.000021
87.	c.1455A>T	p.K485N	missense	1	VUS	0.000000
88.	c.3452C>T	p.A1151V	missense	1	VUS	0.000078
89.	c.1231A>G	p.I411V	missense	1	VUS	0.000000
90.	c.2953A>T	p.K985X	nonsense	1	Pathogenic	0.000000
91.	c.1037G>A	p.R346H	missense	1	VUS	0.000000
92.	c.2873C>T	p.T958I	missense	1	VUS	0.000065
93.	c.2503C>T	p.R835C	missense	1	VUS	0.000024
94.	c.532G>A	p.V178M	missense	1	VUS	0.000020
95.	c.3811C>T	p.R1271X	nonsense	1	VUS	0.000025
96.	c.3614G>C	p.R1205P	missense	1	Likely Pathogenic	0.000000
97.	c.1685C>T	p.A562V	missense	1	VUS	0.000008
98.	c.2265C>A	p.N755K	missense	1	Pathogenic	0.000000
99.	c.1097A>C	p.Q366P	missense	1	VUS	0.000000
100.	c.*26+2T>C		essential splice site	1	Likely Pathogenic	0.000000
101.	c.188G>A	p.R63Q	missense	1	VUS	0.000039
102.	c.731del	p.Lys244Argfs*56	frameshift	1	Pathogenic	0.000000
103.	c.2603-1G>C		essential splice site	1	Pathogenic	0.000000
104.	c.3330+1G>C		essential splice site	1	Pathogenic	0.000000
105.	c.1A>T	p.Met1?	missense	1	Likely Pathogenic	0.000000
106.	c.821+2T>G		essential splice site	1	Pathogenic	0.000000
107.	c.2748G>A	p.W916X	nonsense	1	Pathogenic	0.000000
108.	c.3739G>A	p.D1247N	missense	1	VUS	0.000000
109.	c.1273C>T	p.Q425X	nonsense	1	Pathogenic	0.000000
110.	c.241G>T	p.V81F	missense	1	VUS	0.000000
111.	c.3043dup	p.Ala1015Glyfs*36	frameshift	1	Pathogenic	0.000000
112.	c.1433C>T	p.S478L	missense	1	Likely Pathogenic	0.000017
113.	c.2429_2503delins23	p.Arg810Profs*10	frameshift	1	Pathogenic	0.000000
114.	c.1797del	p.His599Glnfs*3	frameshift	1	Pathogenic	0.000000
115.	c.2690_2696del	p.Gly897Glufs*25	frameshift	1	Pathogenic	0.000000
116.	c.1090+1G>T		essential splice site	1	Pathogenic	0.000000
117.	c.2247C>A	p.Y749X	nonsense	1	Pathogenic	0.000000
118.	c.3490+1G>A		essential splice site	1	Pathogenic	0.000000
119.	c.2065C>T	p.Q689X	nonsense	1	Pathogenic	0.000000
120.	c.1352_1353del	p.Glu451Alafs*23	frameshift	1	Pathogenic	0.000000
121.	c.3617delG		frameshift	1	Pathogenic	0.000000
122.	c.1458G>A	p.W486X	nonsense	1	Pathogenic	0.000000
123.	c.3373G>A	p.V1125M	missense	1	VUS	0.000022
124.	c.2995-1G>A		essential splice site	1	Pathogenic	0.000000
125.	c.3019T>C	p.W1007R	missense	1	VUS	0.000000
126.	c.994G>A	p.E332K	missense	1	VUS	0.000009
127.	c.743_746delACTG		frameshift	1	Pathogenic	0.000000
128.	c.772+1G>A		essential splice site	1	Pathogenic	0.000000
129.	c.1828G>C	p.D610H	missense	1	VUS	0.000058
130.	c.3713T>C	p.L1238P	missense	1	Likely Pathogenic	0.000000
131.	c.2269G>A	p.V757M	missense	1	VUS	0.000066
132.	c.1174G>T	p.A392S	missense	1	VUS	0.000000
133.	c.148A>G	p.S50G	missense	1	VUS	0.000038
134.	c.1038_1042dupCGGCA		frameshift	1	Pathogenic	0.000008
135.	c.2807dup	p.Ala938Glyfs*113	frameshift	1	Pathogenic	0.000000
136.	c.1291G>A	p.D431N	missense	1	VUS	0.000028
137.	c.1789C>T	p.R597W	missense	1	VUS	0.000038
138.	c.256_258del	p.Ser86del	inframe	1	VUS	0.000000
139.	c.3206C>A	p.P1069H	missense	1	Likely Pathogenic	0.000000
140.	c.1898-1G>A		essential splice site	1	Pathogenic	0.000000
141.	c.611_618delinsT	p.Gly204Valfs*94	frameshift	1	Pathogenic	0.000000
142.	c.3357C>A	p.Y1119X	nonsense	1	Pathogenic	0.000000
143.	c.1591G>A	p.G531R	missense	1	Likely Pathogenic	0.000017
144.	c.100_110dup	p.Val38Serfs*5	frameshift	1	Pathogenic	0.000000
145.	c.2718_2719dup	p.Glu907Glyfs*18	frameshift	1	Pathogenic	0.000000
146.	c.2371C>T	p.Q791X	nonsense	1	Pathogenic	0.000000
147.	c.2381C>A	p.P794Q	missense	1	VUS	0.000000
148.	c.1569dup	p.His524Alafs*7	frameshift	1	Pathogenic	0.000000
149.	c.2161_2168del	p.Thr721Profs*23	frameshift	1	Pathogenic	0.000000
150.	c.1376_1377del	p.Pro459Leufs*15	frameshift	1	Pathogenic	0.000000
151.	c.1224-1G>T		essential splice site	1	Pathogenic	0.000000
152.	c.3253G>T	p.E1085X	nonsense	1	Pathogenic	0.000000
153.	c.844C>T	p.R282W	missense	1	Likely Pathogenic	0.000000
154.	c.1021G>C	p.G341R	missense	1	VUS	0.000000
155.	c.811_817delTTCCGCC		frameshift	1	Pathogenic	0.000000
156.	c.506-1G>A		essential splice site	1	Pathogenic	0.000000
157.	c.932C>A	p.S311X	nonsense	1	Pathogenic	0.000000
158.	c.2198G>A	p.R733H	missense	1	VUS	0.000034
159.	c.1999_2000delinsG	p.Leu667AspfsX15	frameshift	1	Pathogenic	0.000000
160.	c.701C>A	p.T234N	missense	1	Likely Pathogenic	0.000000
161.	c.3676C>T	p.R1226C	missense	1	VUS	0.000058
162.	c.1624+1G>A		essential splice site	1	Pathogenic	0.000000
163.	c.2249C>T	p.T750M	missense	1	Likely Pathogenic	0.000024
164.	c.1090+2T>C		essential splice site	1	Pathogenic	0.000000
165.	c.365C>A	p.A122D	missense	1	VUS	0.000000
166.	c.211_212delinsTA	p.Val71*	frameshift	1	Pathogenic	0.000000
167.	c.2968C>G	p.P990A	missense	1	Likely Pathogenic	0.000000
168.	c.1377delC		frameshift	1	Pathogenic	0.000000
169.	c.2584C>T	p.Q862X	nonsense	1	Pathogenic	0.000000
170.	c.3316del	p.Asp1106Thrfs*83	frameshift	1	Pathogenic	0.000000
171.	c.2738-2A>G		essential splice site	1	Pathogenic	0.000000
172.	c.1213A>G	p.M405V	missense	1	VUS	0.000000
173.	c.1090+1G>A		essential splice site	1	Pathogenic	0.000000
174.	c.1405C>T	p.Q469X	nonsense	1	Pathogenic	0.000000
175.	c.2502del	p.Arg835Alafs*2	frameshift	1	Pathogenic	0.000000
176.	c.1756C>G	p.P586A	missense	1	Likely Pathogenic	0.000000
177.	c.2603-2_2603-1delinsGA		essential splice site	1	Pathogenic	0.000000
178.	c.1266_1267insTGAT	p.Ile423*	frameshift	1	Pathogenic	0.000000
179.	c.3614G>A	p.R1205Q	missense	1	VUS	0.000016
180.	c.1457G>A	p.W486X	nonsense	1	Pathogenic	0.000000
181.	c.1072G>A	p.D358N	missense	1	VUS	0.000008
182.	c.3316G>A	p.D1106N	missense	1	VUS	0.000061
183.	c.3572C>T	p.S1191L	missense	1	VUS	0.000016
184.	c.821+1G>A		essential splice site	1	Pathogenic	0.000043
185.	c.2504G>T	p.R835L	missense	1	Likely Pathogenic	0.000074
186.	c.982delG		frameshift	1	Pathogenic	0.000000
187.	c.711C>A	p.Y237X	nonsense	1	Pathogenic	0.000000
188.	c.2304_2308+2delCATCGGT		essential splice site	1	Pathogenic	0.000000
189.	c.1120C>T	p.Q374X	nonsense	1	Pathogenic	0.000000
190.	c.49C>T	p.R17W	missense	1	VUS	0.000023
191.	c.373G>T	p.A125S	missense	1	VUS	0.000000
192.	c.2030C>T	p.P677L	missense	1	VUS	0.000000
193.	c.3728C>G	p.P1243R	missense	1	VUS	0.000000
194.	c.631G>A	p.D211N	missense	1	VUS	0.000009
195.	c.3334_3351del	p.Trp1112_Glu1117del	inframe	1	Likely Pathogenic	0.000000
196.	c.1021_1028del	p.Gly341*	frameshift	1	Pathogenic	0.000000
197.	c.2789del	p.Leu930Argfs*2	frameshift	1	Pathogenic	0.000000
198.	c.255del	p.Ser86Profs*10	frameshift	1	Pathogenic	0.000000
199.	c.1456T>G	p.W486G	missense	1	VUS	0.000000
200.	c.553_562del	p.Lys185Trpfs*12	frameshift	1	Pathogenic	0.000000
201.	c.2512dup	p.Glu838Glyfs*46	frameshift	1	Pathogenic	0.000000
202.	c.2708G>A	p.G903D	missense	1	Likely Pathogenic	0.000000
203.	c.1112C>T	p.P371L	missense	1	VUS	0.000028
204.	c.121dup	p.Arg41Profs*8	frameshift	1	Pathogenic	0.000000
205.	c.2834G>A	p.R945Q	missense	1	VUS	0.000000
206.	c.1303C>T	p.Q435X	nonsense	1	Pathogenic	0.000000
207.	c.1359del	p.Val454Cysfs*12	frameshift	1	Pathogenic	0.000000
208.	c.3624delC		frameshift	1	Pathogenic	0.000000
209.	c.1523_1525delinsT	p.Gln508Leufs*22	frameshift	1	Pathogenic	0.000000
210.	c.2054_2067+11del	p.Lys685Argfs*3	frameshift	1	Pathogenic	0.000000
211.	c.1223+2T>C		essential splice site	1	Pathogenic	0.000000
212.	c.3605delG		frameshift	1	Pathogenic	0.000000
213.	c.1021G>A	p.G341S	missense	1	VUS	0.000025
214.	c.2909G>A	p.R970Q	missense	1	Likely Pathogenic	0.000032
215.	c.2534_2538delGCGTC		frameshift	1	Pathogenic	0.000000
216.	c.3064C>T	p.R1022C	missense	1	VUS	0.000008
217.	c.459delC		frameshift	1	Pathogenic	0.000000
218.	c.2197C>T	p.R733C	missense	1	Likely Pathogenic	0.000085
219.	c.2558delG		frameshift	1	Pathogenic	0.000000
220.	c.1201C>T	p.Q401X	nonsense	1	Pathogenic	0.000000
221.	c.146_148delTCA	p.Ile49del	inframe	1	VUS	0.000039
222.	c.799C>G	p.L267V	missense	1	VUS	0.000080
223.	c.1841A>G	p.Y614C	missense	1	VUS	0.000000
224.	c.2449C>T	p.R817W	missense	1	VUS	0.000000
225.	c.1790G>A	p.R597Q	missense	1	VUS	0.000000
226.	c.351_352del	p.Gly118Argfs*8	frameshift	1	Pathogenic	0.000000
227.	c.3256T>C	p.W1086R	missense	1	VUS	0.000000
228.	c.187C>T	p.R63W	missense	1	VUS	0.000077
229.	c.1471G>A	p.V491M	missense	1	VUS	0.000058
230.	c.655-2del		essential splice site	1	Pathogenic	0.000000
231.	c.3656T>C	p.L1219P	missense	1	VUS	0.000000
232.	c.3364A>T	p.T1122S	missense	1	Likely Pathogenic	0.000000
233.	c.1080G>C	p.K360N	missense	1	VUS	0.000000
234.	c.3792_3793del	p.Cys1264*	frameshift	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.