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.927-2A>G		essential splice site	8	Pathogenic	0.000000
15.	c.2604_2605delinsA	p.S871fs	frameshift	8	Pathogenic	0.000000
16.	c.2864_2865delCT		frameshift	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.2309-1G>A		essential splice site	3	Pathogenic	0.000000
34.	c.3763G>A	p.A1255T	missense	3	VUS	0.000075
35.	c.2545del	p.Val849Serfs*30	frameshift	3	Pathogenic	0.000000
36.	c.3286G>T	p.E1096X	nonsense	3	Pathogenic	0.000000
37.	c.710A>C	p.Y237S	missense	3	Likely Pathogenic	0.000000
38.	c.2210C>T	p.T737M	missense	3	VUS	0.000050
39.	c.2905+1G>A		essential splice site	3	Pathogenic	0.000000
40.	c.1123G>A	p.V375M	missense	3	VUS	0.000009
41.	c.3600_3609delCTGCTGTGCT		frameshift	3	Pathogenic	0.000000
42.	c.3408C>A	p.Y1136X	nonsense	3	Pathogenic	0.000000
43.	c.3277G>T	p.G1093C	missense	3	VUS	0.000020
44.	c.3181C>T	p.Q1061X	nonsense	3	Pathogenic	0.000016
45.	c.1720C>T	p.R574W	missense	3	VUS	0.000054
46.	c.3129C>A	p.Y1043X	nonsense	3	Pathogenic	0.000000
47.	c.1886T>C	p.L629P	missense	2	VUS	0.000000
48.	c.3005G>A	p.R1002Q	missense	2	VUS	0.000046
49.	c.833delG	p.Gly278GlufsX22	frameshift	2	Pathogenic	0.000000
50.	c.2300A>G	p.K767R	missense	2	VUS	0.000016
51.	c.1483C>T	p.R495W	missense	2	Likely Pathogenic	0.000000
52.	c.2308+1G>A		essential splice site	2	Pathogenic	0.000000
53.	c.818G>A	p.R273H	missense	2	VUS	0.000042
54.	c.3582_3593delGGGCTACACTGC		inframe	2	Likely Pathogenic	0.000000
55.	c.2526C>G	p.Y842X	nonsense	2	Pathogenic	0.000000
56.	c.3752A>G	p.Y1251C	missense	2	VUS	0.000000
57.	c.3627+1G>T		essential splice site	2	Pathogenic	0.000000
58.	c.126G>A	p.W42X	nonsense	2	Pathogenic	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.2573G>A	p.S858N	missense	2	Likely Pathogenic	0.000000
62.	c.3271del	p.Asp1091Metfs*98	frameshift	2	Pathogenic	0.000000
63.	c.177_187del	p.Glu60AlafsX49	frameshift	2	Pathogenic	0.000000
64.	c.3455_3466del	p.Ala1152_Lys1155del	inframe	2	Likely Pathogenic	0.000000
65.	c.557C>T	p.P186L	missense	2	VUS	0.000047
66.	c.443dup	p.Ala149Serfs*4	frameshift	2	Pathogenic	0.000000
67.	c.2219G>C	p.G740A	missense	2	VUS	0.000000
68.	c.3470C>T	p.P1157L	missense	2	VUS	0.000093
69.	c.2905C>T	p.Q969X	nonsense	2	Pathogenic	0.000000
70.	c.1828G>A	p.D610N	missense	2	VUS	0.000000
71.	c.2432A>G	p.K811R	missense	2	VUS	0.000000
72.	c.747C>A	p.C249X	nonsense	2	Pathogenic	0.000000
73.	c.1505G>A	p.R502Q	missense	2	Pathogenic	0.000000
74.	c.25+1G>A		essential splice site	2	Pathogenic	0.000000
75.	c.3751T>C	p.Y1251H	missense	2	VUS	0.000000
76.	c.2512dup	p.Glu838Glyfs*46	frameshift	1	Pathogenic	0.000000
77.	c.2708G>A	p.G903D	missense	1	Likely Pathogenic	0.000000
78.	c.1112C>T	p.P371L	missense	1	VUS	0.000028
79.	c.121dup	p.Arg41Profs*8	frameshift	1	Pathogenic	0.000000
80.	c.2834G>A	p.R945Q	missense	1	VUS	0.000000
81.	c.1303C>T	p.Q435X	nonsense	1	Pathogenic	0.000000
82.	c.1359del	p.Val454Cysfs*12	frameshift	1	Pathogenic	0.000000
83.	c.3624delC		frameshift	1	Pathogenic	0.000000
84.	c.1523_1525delinsT	p.Gln508Leufs*22	frameshift	1	Pathogenic	0.000000
85.	c.2054_2067+11del	p.Lys685Argfs*3	frameshift	1	Pathogenic	0.000000
86.	c.1223+2T>C		essential splice site	1	Pathogenic	0.000000
87.	c.3605delG		frameshift	1	Pathogenic	0.000000
88.	c.1021G>A	p.G341S	missense	1	VUS	0.000025
89.	c.2909G>A	p.R970Q	missense	1	Likely Pathogenic	0.000032
90.	c.2534_2538delGCGTC		frameshift	1	Pathogenic	0.000000
91.	c.3064C>T	p.R1022C	missense	1	VUS	0.000008
92.	c.459delC		frameshift	1	Pathogenic	0.000000
93.	c.2197C>T	p.R733C	missense	1	Likely Pathogenic	0.000085
94.	c.2558delG		frameshift	1	Pathogenic	0.000000
95.	c.1201C>T	p.Q401X	nonsense	1	Pathogenic	0.000000
96.	c.146_148delTCA	p.Ile49del	inframe	1	VUS	0.000039
97.	c.799C>G	p.L267V	missense	1	VUS	0.000080
98.	c.1841A>G	p.Y614C	missense	1	VUS	0.000000
99.	c.2449C>T	p.R817W	missense	1	VUS	0.000000
100.	c.1790G>A	p.R597Q	missense	1	VUS	0.000000
101.	c.351_352del	p.Gly118Argfs*8	frameshift	1	Pathogenic	0.000000
102.	c.3256T>C	p.W1086R	missense	1	VUS	0.000000
103.	c.187C>T	p.R63W	missense	1	VUS	0.000077
104.	c.1471G>A	p.V491M	missense	1	VUS	0.000058
105.	c.655-2del		essential splice site	1	Pathogenic	0.000000
106.	c.3656T>C	p.L1219P	missense	1	VUS	0.000000
107.	c.3364A>T	p.T1122S	missense	1	Likely Pathogenic	0.000000
108.	c.1080G>C	p.K360N	missense	1	VUS	0.000000
109.	c.3792_3793del	p.Cys1264*	frameshift	1	Likely Pathogenic	0.000000
110.	c.2149_2737del	p.Leu717Alafs*11	frameshift	1	Pathogenic	0.000000
111.	c.1153G>A	p.V385M	missense	1	VUS	0.000010
112.	c.177dup	p.Glu60Argfs*53	frameshift	1	Pathogenic	0.000000
113.	c.2953A>G	p.K985E	missense	1	Pathogenic	0.000000
114.	c.1351+1G>A		essential splice site	1	Pathogenic	0.000000
115.	c.391dup	p.Ala131Glyfs*22	frameshift	1	Pathogenic	0.000000
116.	c.3297dup	p.Tyr1100Valfs*49	frameshift	1	Pathogenic	0.000000
117.	c.1731G>C	p.W577C	missense	1	VUS	0.000000
118.	c.2188del	p.Thr730Profs*24	frameshift	1	Pathogenic	0.000000
119.	c.1404del	p.Gln469Serfs*19	frameshift	1	Pathogenic	0.000000
120.	c.3257G>A	p.W1086X	nonsense	1	Pathogenic	0.000021
121.	c.1455A>T	p.K485N	missense	1	VUS	0.000000
122.	c.3452C>T	p.A1151V	missense	1	VUS	0.000078
123.	c.1231A>G	p.I411V	missense	1	VUS	0.000000
124.	c.2953A>T	p.K985X	nonsense	1	Pathogenic	0.000000
125.	c.1037G>A	p.R346H	missense	1	VUS	0.000000
126.	c.2873C>T	p.T958I	missense	1	VUS	0.000065
127.	c.2503C>T	p.R835C	missense	1	VUS	0.000024
128.	c.532G>A	p.V178M	missense	1	VUS	0.000020
129.	c.3811C>T	p.R1271X	nonsense	1	VUS	0.000025
130.	c.731del	p.Lys244Argfs*56	frameshift	1	Pathogenic	0.000000
131.	c.3614G>C	p.R1205P	missense	1	Likely Pathogenic	0.000000
132.	c.1685C>T	p.A562V	missense	1	VUS	0.000008
133.	c.2265C>A	p.N755K	missense	1	Pathogenic	0.000000
134.	c.1097A>C	p.Q366P	missense	1	VUS	0.000000
135.	c.*26+2T>C		essential splice site	1	Likely Pathogenic	0.000000
136.	c.188G>A	p.R63Q	missense	1	VUS	0.000039
137.	c.1433C>T	p.S478L	missense	1	Likely Pathogenic	0.000017
138.	c.2603-1G>C		essential splice site	1	Pathogenic	0.000000
139.	c.3330+1G>C		essential splice site	1	Pathogenic	0.000000
140.	c.1A>T	p.Met1?	missense	1	Likely Pathogenic	0.000000
141.	c.821+2T>G		essential splice site	1	Pathogenic	0.000000
142.	c.2748G>A	p.W916X	nonsense	1	Pathogenic	0.000000
143.	c.3739G>A	p.D1247N	missense	1	VUS	0.000000
144.	c.1273C>T	p.Q425X	nonsense	1	Pathogenic	0.000000
145.	c.241G>T	p.V81F	missense	1	VUS	0.000000
146.	c.3043dup	p.Ala1015Glyfs*36	frameshift	1	Pathogenic	0.000000
147.	c.2247C>A	p.Y749X	nonsense	1	Pathogenic	0.000000
148.	c.2429_2503delins23	p.Arg810Profs*10	frameshift	1	Pathogenic	0.000000
149.	c.1797del	p.His599Glnfs*3	frameshift	1	Pathogenic	0.000000
150.	c.2690_2696del	p.Gly897Glufs*25	frameshift	1	Pathogenic	0.000000
151.	c.1090+1G>T		essential splice site	1	Pathogenic	0.000000
152.	c.3490+1G>A		essential splice site	1	Pathogenic	0.000000
153.	c.2065C>T	p.Q689X	nonsense	1	Pathogenic	0.000000
154.	c.1352_1353del	p.Glu451Alafs*23	frameshift	1	Pathogenic	0.000000
155.	c.3617delG		frameshift	1	Pathogenic	0.000000
156.	c.1458G>A	p.W486X	nonsense	1	Pathogenic	0.000000
157.	c.3373G>A	p.V1125M	missense	1	VUS	0.000022
158.	c.2995-1G>A		essential splice site	1	Pathogenic	0.000000
159.	c.3019T>C	p.W1007R	missense	1	VUS	0.000000
160.	c.994G>A	p.E332K	missense	1	VUS	0.000009
161.	c.743_746delACTG		frameshift	1	Pathogenic	0.000000
162.	c.148A>G	p.S50G	missense	1	VUS	0.000038
163.	c.772+1G>A		essential splice site	1	Pathogenic	0.000000
164.	c.1828G>C	p.D610H	missense	1	VUS	0.000058
165.	c.3713T>C	p.L1238P	missense	1	Likely Pathogenic	0.000000
166.	c.2269G>A	p.V757M	missense	1	VUS	0.000066
167.	c.1174G>T	p.A392S	missense	1	VUS	0.000000
168.	c.100_110dup	p.Val38Serfs*5	frameshift	1	Pathogenic	0.000000
169.	c.1038_1042dupCGGCA		frameshift	1	Pathogenic	0.000008
170.	c.2807dup	p.Ala938Glyfs*113	frameshift	1	Pathogenic	0.000000
171.	c.1291G>A	p.D431N	missense	1	VUS	0.000028
172.	c.1789C>T	p.R597W	missense	1	VUS	0.000038
173.	c.256_258del	p.Ser86del	inframe	1	VUS	0.000000
174.	c.3206C>A	p.P1069H	missense	1	Likely Pathogenic	0.000000
175.	c.1898-1G>A		essential splice site	1	Pathogenic	0.000000
176.	c.611_618delinsT	p.Gly204Valfs*94	frameshift	1	Pathogenic	0.000000
177.	c.3357C>A	p.Y1119X	nonsense	1	Pathogenic	0.000000
178.	c.1591G>A	p.G531R	missense	1	Likely Pathogenic	0.000017
179.	c.2718_2719dup	p.Glu907Glyfs*18	frameshift	1	Pathogenic	0.000000
180.	c.2371C>T	p.Q791X	nonsense	1	Pathogenic	0.000000
181.	c.1376_1377del	p.Pro459Leufs*15	frameshift	1	Pathogenic	0.000000
182.	c.2381C>A	p.P794Q	missense	1	VUS	0.000000
183.	c.1569dup	p.His524Alafs*7	frameshift	1	Pathogenic	0.000000
184.	c.2161_2168del	p.Thr721Profs*23	frameshift	1	Pathogenic	0.000000
185.	c.1224-1G>T		essential splice site	1	Pathogenic	0.000000
186.	c.3253G>T	p.E1085X	nonsense	1	Pathogenic	0.000000
187.	c.844C>T	p.R282W	missense	1	Likely Pathogenic	0.000000
188.	c.1021G>C	p.G341R	missense	1	VUS	0.000000
189.	c.932C>A	p.S311X	nonsense	1	Pathogenic	0.000000
190.	c.2198G>A	p.R733H	missense	1	VUS	0.000034
191.	c.811_817delTTCCGCC		frameshift	1	Pathogenic	0.000000
192.	c.506-1G>A		essential splice site	1	Pathogenic	0.000000
193.	c.1999_2000delinsG	p.Leu667AspfsX15	frameshift	1	Pathogenic	0.000000
194.	c.701C>A	p.T234N	missense	1	Likely Pathogenic	0.000000
195.	c.3676C>T	p.R1226C	missense	1	VUS	0.000058
196.	c.1624+1G>A		essential splice site	1	Pathogenic	0.000000
197.	c.2249C>T	p.T750M	missense	1	Likely Pathogenic	0.000024
198.	c.1090+2T>C		essential splice site	1	Pathogenic	0.000000
199.	c.365C>A	p.A122D	missense	1	VUS	0.000000
200.	c.211_212delinsTA	p.Val71*	frameshift	1	Pathogenic	0.000000
201.	c.2968C>G	p.P990A	missense	1	Likely Pathogenic	0.000000
202.	c.1377delC		frameshift	1	Pathogenic	0.000000
203.	c.2584C>T	p.Q862X	nonsense	1	Pathogenic	0.000000
204.	c.3316del	p.Asp1106Thrfs*83	frameshift	1	Pathogenic	0.000000
205.	c.2738-2A>G		essential splice site	1	Pathogenic	0.000000
206.	c.1213A>G	p.M405V	missense	1	VUS	0.000000
207.	c.1090+1G>A		essential splice site	1	Pathogenic	0.000000
208.	c.1405C>T	p.Q469X	nonsense	1	Pathogenic	0.000000
209.	c.2502del	p.Arg835Alafs*2	frameshift	1	Pathogenic	0.000000
210.	c.1756C>G	p.P586A	missense	1	Likely Pathogenic	0.000000
211.	c.2603-2_2603-1delinsGA		essential splice site	1	Pathogenic	0.000000
212.	c.1457G>A	p.W486X	nonsense	1	Pathogenic	0.000000
213.	c.1266_1267insTGAT	p.Ile423*	frameshift	1	Pathogenic	0.000000
214.	c.3614G>A	p.R1205Q	missense	1	VUS	0.000016
215.	c.1072G>A	p.D358N	missense	1	VUS	0.000008
216.	c.3316G>A	p.D1106N	missense	1	VUS	0.000061
217.	c.3572C>T	p.S1191L	missense	1	VUS	0.000016
218.	c.821+1G>A		essential splice site	1	Pathogenic	0.000043
219.	c.2504G>T	p.R835L	missense	1	Likely Pathogenic	0.000074
220.	c.982delG		frameshift	1	Pathogenic	0.000000
221.	c.711C>A	p.Y237X	nonsense	1	Pathogenic	0.000000
222.	c.2304_2308+2delCATCGGT		essential splice site	1	Pathogenic	0.000000
223.	c.1120C>T	p.Q374X	nonsense	1	Pathogenic	0.000000
224.	c.49C>T	p.R17W	missense	1	VUS	0.000023
225.	c.373G>T	p.A125S	missense	1	VUS	0.000000
226.	c.2030C>T	p.P677L	missense	1	VUS	0.000000
227.	c.3728C>G	p.P1243R	missense	1	VUS	0.000000
228.	c.631G>A	p.D211N	missense	1	VUS	0.000009
229.	c.3334_3351del	p.Trp1112_Glu1117del	inframe	1	Likely Pathogenic	0.000000
230.	c.1021_1028del	p.Gly341*	frameshift	1	Pathogenic	0.000000
231.	c.2789del	p.Leu930Argfs*2	frameshift	1	Pathogenic	0.000000
232.	c.255del	p.Ser86Profs*10	frameshift	1	Pathogenic	0.000000
233.	c.1456T>G	p.W486G	missense	1	VUS	0.000000
234.	c.553_562del	p.Lys185Trpfs*12	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.