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.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.3065G>C	p.R1022P	missense	5	Likely Pathogenic	0.000025
21.	c.2459G>A	p.R820Q	missense	5	VUS	0.000016
22.	c.2308G>A	p.D770N	missense	5	Likely Pathogenic	0.000008
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.3697C>T	p.Q1233X	nonsense	4	Likely Pathogenic	0.000008
28.	c.821+2T>C		essential splice site	4	Pathogenic	0.000000
29.	c.442G>A	p.G148R	missense	4	Likely Pathogenic	0.000042
30.	c.2556_2557delinsTCT	p.Gly853fs	frameshift	4	Pathogenic	0.000000
31.	c.3798C>G	p.C1266W	missense	4	VUS	0.000000
32.	c.1484G>A	p.R495Q	missense	4	Likely Pathogenic	0.000008
33.	c.3286G>T	p.E1096X	nonsense	3	Pathogenic	0.000000
34.	c.2210C>T	p.T737M	missense	3	VUS	0.000050
35.	c.710A>C	p.Y237S	missense	3	Likely Pathogenic	0.000000
36.	c.2905+1G>A		essential splice site	3	Pathogenic	0.000000
37.	c.1123G>A	p.V375M	missense	3	VUS	0.000009
38.	c.3763G>A	p.A1255T	missense	3	VUS	0.000075
39.	c.3408C>A	p.Y1136X	nonsense	3	Pathogenic	0.000000
40.	c.3600_3609delCTGCTGTGCT		frameshift	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.2545del	p.Val849Serfs*30	frameshift	3	Pathogenic	0.000000
47.	c.2308+1G>A		essential splice site	2	Pathogenic	0.000000
48.	c.818G>A	p.R273H	missense	2	VUS	0.000042
49.	c.3582_3593delGGGCTACACTGC		inframe	2	Likely Pathogenic	0.000000
50.	c.2526C>G	p.Y842X	nonsense	2	Pathogenic	0.000000
51.	c.3752A>G	p.Y1251C	missense	2	VUS	0.000000
52.	c.126G>A	p.W42X	nonsense	2	Pathogenic	0.000000
53.	c.2905+2dup		essential splice site	2	Likely Pathogenic	0.000000
54.	c.2524dup	p.Tyr842Leufs*42	frameshift	2	Pathogenic	0.000000
55.	c.2573G>A	p.S858N	missense	2	Likely Pathogenic	0.000000
56.	c.3271del	p.Asp1091Metfs*98	frameshift	2	Pathogenic	0.000000
57.	c.177_187del	p.Glu60AlafsX49	frameshift	2	Pathogenic	0.000000
58.	c.3455_3466del	p.Ala1152_Lys1155del	inframe	2	Likely Pathogenic	0.000000
59.	c.557C>T	p.P186L	missense	2	VUS	0.000047
60.	c.443dup	p.Ala149Serfs*4	frameshift	2	Pathogenic	0.000000
61.	c.2219G>C	p.G740A	missense	2	VUS	0.000000
62.	c.3470C>T	p.P1157L	missense	2	VUS	0.000093
63.	c.2905C>T	p.Q969X	nonsense	2	Pathogenic	0.000000
64.	c.747C>A	p.C249X	nonsense	2	Pathogenic	0.000000
65.	c.1828G>A	p.D610N	missense	2	VUS	0.000000
66.	c.2432A>G	p.K811R	missense	2	VUS	0.000000
67.	c.1505G>A	p.R502Q	missense	2	Pathogenic	0.000000
68.	c.25+1G>A		essential splice site	2	Pathogenic	0.000000
69.	c.3751T>C	p.Y1251H	missense	2	VUS	0.000000
70.	c.1886T>C	p.L629P	missense	2	VUS	0.000000
71.	c.3627+1G>T		essential splice site	2	Pathogenic	0.000000
72.	c.3005G>A	p.R1002Q	missense	2	VUS	0.000046
73.	c.833delG	p.Gly278GlufsX22	frameshift	2	Pathogenic	0.000000
74.	c.2300A>G	p.K767R	missense	2	VUS	0.000016
75.	c.1483C>T	p.R495W	missense	2	Likely Pathogenic	0.000000
76.	c.3452C>T	p.A1151V	missense	1	VUS	0.000078
77.	c.1231A>G	p.I411V	missense	1	VUS	0.000000
78.	c.3257G>A	p.W1086X	nonsense	1	Pathogenic	0.000021
79.	c.1455A>T	p.K485N	missense	1	VUS	0.000000
80.	c.3676C>T	p.R1226C	missense	1	VUS	0.000058
81.	c.1037G>A	p.R346H	missense	1	VUS	0.000000
82.	c.2953A>T	p.K985X	nonsense	1	Pathogenic	0.000000
83.	c.2503C>T	p.R835C	missense	1	VUS	0.000024
84.	c.532G>A	p.V178M	missense	1	VUS	0.000020
85.	c.2873C>T	p.T958I	missense	1	VUS	0.000065
86.	c.188G>A	p.R63Q	missense	1	VUS	0.000039
87.	c.731del	p.Lys244Argfs*56	frameshift	1	Pathogenic	0.000000
88.	c.3614G>C	p.R1205P	missense	1	Likely Pathogenic	0.000000
89.	c.1685C>T	p.A562V	missense	1	VUS	0.000008
90.	c.2265C>A	p.N755K	missense	1	Pathogenic	0.000000
91.	c.1097A>C	p.Q366P	missense	1	VUS	0.000000
92.	c.*26+2T>C		essential splice site	1	Likely Pathogenic	0.000000
93.	c.821+2T>G		essential splice site	1	Pathogenic	0.000000
94.	c.2748G>A	p.W916X	nonsense	1	Pathogenic	0.000000
95.	c.3739G>A	p.D1247N	missense	1	VUS	0.000000
96.	c.1273C>T	p.Q425X	nonsense	1	Pathogenic	0.000000
97.	c.241G>T	p.V81F	missense	1	VUS	0.000000
98.	c.3043dup	p.Ala1015Glyfs*36	frameshift	1	Pathogenic	0.000000
99.	c.1433C>T	p.S478L	missense	1	Likely Pathogenic	0.000017
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.1A>T	p.Met1?	missense	1	Likely Pathogenic	0.000000
103.	c.1797del	p.His599Glnfs*3	frameshift	1	Pathogenic	0.000000
104.	c.2690_2696del	p.Gly897Glufs*25	frameshift	1	Pathogenic	0.000000
105.	c.1090+1G>T		essential splice site	1	Pathogenic	0.000000
106.	c.2247C>A	p.Y749X	nonsense	1	Pathogenic	0.000000
107.	c.2429_2503delins23	p.Arg810Profs*10	frameshift	1	Pathogenic	0.000000
108.	c.3617delG		frameshift	1	Pathogenic	0.000000
109.	c.1458G>A	p.W486X	nonsense	1	Pathogenic	0.000000
110.	c.3490+1G>A		essential splice site	1	Pathogenic	0.000000
111.	c.2065C>T	p.Q689X	nonsense	1	Pathogenic	0.000000
112.	c.1352_1353del	p.Glu451Alafs*23	frameshift	1	Pathogenic	0.000000
113.	c.2995-1G>A		essential splice site	1	Pathogenic	0.000000
114.	c.3373G>A	p.V1125M	missense	1	VUS	0.000022
115.	c.743_746delACTG		frameshift	1	Pathogenic	0.000000
116.	c.3019T>C	p.W1007R	missense	1	VUS	0.000000
117.	c.994G>A	p.E332K	missense	1	VUS	0.000009
118.	c.2269G>A	p.V757M	missense	1	VUS	0.000066
119.	c.1174G>T	p.A392S	missense	1	VUS	0.000000
120.	c.148A>G	p.S50G	missense	1	VUS	0.000038
121.	c.772+1G>A		essential splice site	1	Pathogenic	0.000000
122.	c.1828G>C	p.D610H	missense	1	VUS	0.000058
123.	c.1898-1G>A		essential splice site	1	Pathogenic	0.000000
124.	c.611_618delinsT	p.Gly204Valfs*94	frameshift	1	Pathogenic	0.000000
125.	c.3357C>A	p.Y1119X	nonsense	1	Pathogenic	0.000000
126.	c.1591G>A	p.G531R	missense	1	Likely Pathogenic	0.000017
127.	c.100_110dup	p.Val38Serfs*5	frameshift	1	Pathogenic	0.000000
128.	c.1038_1042dupCGGCA		frameshift	1	Pathogenic	0.000008
129.	c.2807dup	p.Ala938Glyfs*113	frameshift	1	Pathogenic	0.000000
130.	c.1291G>A	p.D431N	missense	1	VUS	0.000028
131.	c.1789C>T	p.R597W	missense	1	VUS	0.000038
132.	c.256_258del	p.Ser86del	inframe	1	VUS	0.000000
133.	c.3206C>A	p.P1069H	missense	1	Likely Pathogenic	0.000000
134.	c.2371C>T	p.Q791X	nonsense	1	Pathogenic	0.000000
135.	c.2718_2719dup	p.Glu907Glyfs*18	frameshift	1	Pathogenic	0.000000
136.	c.2161_2168del	p.Thr721Profs*23	frameshift	1	Pathogenic	0.000000
137.	c.1376_1377del	p.Pro459Leufs*15	frameshift	1	Pathogenic	0.000000
138.	c.2381C>A	p.P794Q	missense	1	VUS	0.000000
139.	c.1569dup	p.His524Alafs*7	frameshift	1	Pathogenic	0.000000
140.	c.3656T>C	p.L1219P	missense	1	VUS	0.000000
141.	c.1224-1G>T		essential splice site	1	Pathogenic	0.000000
142.	c.3253G>T	p.E1085X	nonsense	1	Pathogenic	0.000000
143.	c.1021G>C	p.G341R	missense	1	VUS	0.000000
144.	c.844C>T	p.R282W	missense	1	Likely 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.932C>A	p.S311X	nonsense	1	Pathogenic	0.000000
148.	c.2198G>A	p.R733H	missense	1	VUS	0.000034
149.	c.2249C>T	p.T750M	missense	1	Likely Pathogenic	0.000024
150.	c.1090+2T>C		essential splice site	1	Pathogenic	0.000000
151.	c.365C>A	p.A122D	missense	1	VUS	0.000000
152.	c.1999_2000delinsG	p.Leu667AspfsX15	frameshift	1	Pathogenic	0.000000
153.	c.701C>A	p.T234N	missense	1	Likely Pathogenic	0.000000
154.	c.1624+1G>A		essential splice site	1	Pathogenic	0.000000
155.	c.3316del	p.Asp1106Thrfs*83	frameshift	1	Pathogenic	0.000000
156.	c.2738-2A>G		essential splice site	1	Pathogenic	0.000000
157.	c.1213A>G	p.M405V	missense	1	VUS	0.000000
158.	c.211_212delinsTA	p.Val71*	frameshift	1	Pathogenic	0.000000
159.	c.2968C>G	p.P990A	missense	1	Likely Pathogenic	0.000000
160.	c.1377delC		frameshift	1	Pathogenic	0.000000
161.	c.2584C>T	p.Q862X	nonsense	1	Pathogenic	0.000000
162.	c.1405C>T	p.Q469X	nonsense	1	Pathogenic	0.000000
163.	c.2502del	p.Arg835Alafs*2	frameshift	1	Pathogenic	0.000000
164.	c.1756C>G	p.P586A	missense	1	Likely Pathogenic	0.000000
165.	c.2603-2_2603-1delinsGA		essential splice site	1	Pathogenic	0.000000
166.	c.3811C>T	p.R1271X	nonsense	1	VUS	0.000025
167.	c.1090+1G>A		essential splice site	1	Pathogenic	0.000000
168.	c.1266_1267insTGAT	p.Ile423*	frameshift	1	Pathogenic	0.000000
169.	c.3614G>A	p.R1205Q	missense	1	VUS	0.000016
170.	c.1457G>A	p.W486X	nonsense	1	Pathogenic	0.000000
171.	c.3316G>A	p.D1106N	missense	1	VUS	0.000061
172.	c.3572C>T	p.S1191L	missense	1	VUS	0.000016
173.	c.1072G>A	p.D358N	missense	1	VUS	0.000008
174.	c.982delG		frameshift	1	Pathogenic	0.000000
175.	c.711C>A	p.Y237X	nonsense	1	Pathogenic	0.000000
176.	c.2304_2308+2delCATCGGT		essential splice site	1	Pathogenic	0.000000
177.	c.821+1G>A		essential splice site	1	Pathogenic	0.000043
178.	c.2504G>T	p.R835L	missense	1	Likely Pathogenic	0.000074
179.	c.373G>T	p.A125S	missense	1	VUS	0.000000
180.	c.2030C>T	p.P677L	missense	1	VUS	0.000000
181.	c.3728C>G	p.P1243R	missense	1	VUS	0.000000
182.	c.631G>A	p.D211N	missense	1	VUS	0.000009
183.	c.1120C>T	p.Q374X	nonsense	1	Pathogenic	0.000000
184.	c.49C>T	p.R17W	missense	1	VUS	0.000023
185.	c.255del	p.Ser86Profs*10	frameshift	1	Pathogenic	0.000000
186.	c.1456T>G	p.W486G	missense	1	VUS	0.000000
187.	c.553_562del	p.Lys185Trpfs*12	frameshift	1	Pathogenic	0.000000
188.	c.3334_3351del	p.Trp1112_Glu1117del	inframe	1	Likely Pathogenic	0.000000
189.	c.1021_1028del	p.Gly341*	frameshift	1	Pathogenic	0.000000
190.	c.2789del	p.Leu930Argfs*2	frameshift	1	Pathogenic	0.000000
191.	c.1112C>T	p.P371L	missense	1	VUS	0.000028
192.	c.121dup	p.Arg41Profs*8	frameshift	1	Pathogenic	0.000000
193.	c.2834G>A	p.R945Q	missense	1	VUS	0.000000
194.	c.1303C>T	p.Q435X	nonsense	1	Pathogenic	0.000000
195.	c.2512dup	p.Glu838Glyfs*46	frameshift	1	Pathogenic	0.000000
196.	c.2708G>A	p.G903D	missense	1	Likely Pathogenic	0.000000
197.	c.1523_1525delinsT	p.Gln508Leufs*22	frameshift	1	Pathogenic	0.000000
198.	c.3713T>C	p.L1238P	missense	1	Likely Pathogenic	0.000000
199.	c.2054_2067+11del	p.Lys685Argfs*3	frameshift	1	Pathogenic	0.000000
200.	c.1359del	p.Val454Cysfs*12	frameshift	1	Pathogenic	0.000000
201.	c.3624delC		frameshift	1	Pathogenic	0.000000
202.	c.1223+2T>C		essential splice site	1	Pathogenic	0.000000
203.	c.3605delG		frameshift	1	Pathogenic	0.000000
204.	c.2909G>A	p.R970Q	missense	1	Likely Pathogenic	0.000032
205.	c.2534_2538delGCGTC		frameshift	1	Pathogenic	0.000000
206.	c.3064C>T	p.R1022C	missense	1	VUS	0.000008
207.	c.1021G>A	p.G341S	missense	1	VUS	0.000025
208.	c.1201C>T	p.Q401X	nonsense	1	Pathogenic	0.000000
209.	c.146_148delTCA	p.Ile49del	inframe	1	VUS	0.000039
210.	c.799C>G	p.L267V	missense	1	VUS	0.000080
211.	c.1841A>G	p.Y614C	missense	1	VUS	0.000000
212.	c.2449C>T	p.R817W	missense	1	VUS	0.000000
213.	c.459delC		frameshift	1	Pathogenic	0.000000
214.	c.2197C>T	p.R733C	missense	1	Likely Pathogenic	0.000085
215.	c.2558delG		frameshift	1	Pathogenic	0.000000
216.	c.3364A>T	p.T1122S	missense	1	Likely Pathogenic	0.000000
217.	c.1080G>C	p.K360N	missense	1	VUS	0.000000
218.	c.3792_3793del	p.Cys1264*	frameshift	1	Likely Pathogenic	0.000000
219.	c.1790G>A	p.R597Q	missense	1	VUS	0.000000
220.	c.351_352del	p.Gly118Argfs*8	frameshift	1	Pathogenic	0.000000
221.	c.3256T>C	p.W1086R	missense	1	VUS	0.000000
222.	c.187C>T	p.R63W	missense	1	VUS	0.000077
223.	c.1471G>A	p.V491M	missense	1	VUS	0.000058
224.	c.655-2del		essential splice site	1	Pathogenic	0.000000
225.	c.391dup	p.Ala131Glyfs*22	frameshift	1	Pathogenic	0.000000
226.	c.3297dup	p.Tyr1100Valfs*49	frameshift	1	Pathogenic	0.000000
227.	c.2149_2737del	p.Leu717Alafs*11	frameshift	1	Pathogenic	0.000000
228.	c.1153G>A	p.V385M	missense	1	VUS	0.000010
229.	c.177dup	p.Glu60Argfs*53	frameshift	1	Pathogenic	0.000000
230.	c.2953A>G	p.K985E	missense	1	Pathogenic	0.000000
231.	c.1351+1G>A		essential splice site	1	Pathogenic	0.000000
232.	c.1404del	p.Gln469Serfs*19	frameshift	1	Pathogenic	0.000000
233.	c.1731G>C	p.W577C	missense	1	VUS	0.000000
234.	c.2188del	p.Thr730Profs*24	frameshift	1	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.