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.3613C>T	p.R1205W	missense	10	Likely Pathogenic	0.000016
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.2864_2865delCT		frameshift	8	Pathogenic	0.000000
15.	c.927-2A>G		essential splice site	8	Pathogenic	0.000000
16.	c.2604_2605delinsA	p.S871fs	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.3798C>G	p.C1266W	missense	4	VUS	0.000000
26.	c.2556_2557delinsTCT	p.Gly853fs	frameshift	4	Pathogenic	0.000000
27.	c.1484G>A	p.R495Q	missense	4	Likely Pathogenic	0.000008
28.	c.484C>T	p.Q162X	nonsense	4	Pathogenic	0.000000
29.	c.3697C>T	p.Q1233X	nonsense	4	Likely Pathogenic	0.000008
30.	c.3163A>T	p.K1055X	nonsense	4	Pathogenic	0.000000
31.	c.821+2T>C		essential splice site	4	Pathogenic	0.000000
32.	c.442G>A	p.G148R	missense	4	Likely Pathogenic	0.000042
33.	c.3286G>T	p.E1096X	nonsense	3	Pathogenic	0.000000
34.	c.3181C>T	p.Q1061X	nonsense	3	Pathogenic	0.000016
35.	c.3129C>A	p.Y1043X	nonsense	3	Pathogenic	0.000000
36.	c.2309-1G>A		essential splice site	3	Pathogenic	0.000000
37.	c.1720C>T	p.R574W	missense	3	VUS	0.000054
38.	c.1123G>A	p.V375M	missense	3	VUS	0.000009
39.	c.2545del	p.Val849Serfs*30	frameshift	3	Pathogenic	0.000000
40.	c.3763G>A	p.A1255T	missense	3	VUS	0.000075
41.	c.3600_3609delCTGCTGTGCT		frameshift	3	Pathogenic	0.000000
42.	c.3408C>A	p.Y1136X	nonsense	3	Pathogenic	0.000000
43.	c.710A>C	p.Y237S	missense	3	Likely Pathogenic	0.000000
44.	c.3277G>T	p.G1093C	missense	3	VUS	0.000020
45.	c.2210C>T	p.T737M	missense	3	VUS	0.000050
46.	c.2905+1G>A		essential splice site	3	Pathogenic	0.000000
47.	c.3455_3466del	p.Ala1152_Lys1155del	inframe	2	Likely Pathogenic	0.000000
48.	c.557C>T	p.P186L	missense	2	VUS	0.000047
49.	c.3271del	p.Asp1091Metfs*98	frameshift	2	Pathogenic	0.000000
50.	c.177_187del	p.Glu60AlafsX49	frameshift	2	Pathogenic	0.000000
51.	c.2573G>A	p.S858N	missense	2	Likely Pathogenic	0.000000
52.	c.2219G>C	p.G740A	missense	2	VUS	0.000000
53.	c.2905C>T	p.Q969X	nonsense	2	Pathogenic	0.000000
54.	c.3751T>C	p.Y1251H	missense	2	VUS	0.000000
55.	c.1828G>A	p.D610N	missense	2	VUS	0.000000
56.	c.1886T>C	p.L629P	missense	2	VUS	0.000000
57.	c.2432A>G	p.K811R	missense	2	VUS	0.000000
58.	c.1505G>A	p.R502Q	missense	2	Pathogenic	0.000000
59.	c.126G>A	p.W42X	nonsense	2	Pathogenic	0.000000
60.	c.833delG	p.Gly278GlufsX22	frameshift	2	Pathogenic	0.000000
61.	c.3582_3593delGGGCTACACTGC		inframe	2	Likely Pathogenic	0.000000
62.	c.3005G>A	p.R1002Q	missense	2	VUS	0.000046
63.	c.2300A>G	p.K767R	missense	2	VUS	0.000016
64.	c.1483C>T	p.R495W	missense	2	Likely Pathogenic	0.000000
65.	c.443dup	p.Ala149Serfs*4	frameshift	2	Pathogenic	0.000000
66.	c.818G>A	p.R273H	missense	2	VUS	0.000042
67.	c.2308+1G>A		essential splice site	2	Pathogenic	0.000000
68.	c.747C>A	p.C249X	nonsense	2	Pathogenic	0.000000
69.	c.3470C>T	p.P1157L	missense	2	VUS	0.000093
70.	c.25+1G>A		essential splice site	2	Pathogenic	0.000000
71.	c.2526C>G	p.Y842X	nonsense	2	Pathogenic	0.000000
72.	c.3752A>G	p.Y1251C	missense	2	VUS	0.000000
73.	c.2905+2dup		essential splice site	2	Likely Pathogenic	0.000000
74.	c.2524dup	p.Tyr842Leufs*42	frameshift	2	Pathogenic	0.000000
75.	c.3627+1G>T		essential splice site	2	Pathogenic	0.000000
76.	c.2584C>T	p.Q862X	nonsense	1	Pathogenic	0.000000
77.	c.3316del	p.Asp1106Thrfs*83	frameshift	1	Pathogenic	0.000000
78.	c.2738-2A>G		essential splice site	1	Pathogenic	0.000000
79.	c.2198G>A	p.R733H	missense	1	VUS	0.000034
80.	c.2968C>G	p.P990A	missense	1	Likely Pathogenic	0.000000
81.	c.1624+1G>A		essential splice site	1	Pathogenic	0.000000
82.	c.2249C>T	p.T750M	missense	1	Likely Pathogenic	0.000024
83.	c.1405C>T	p.Q469X	nonsense	1	Pathogenic	0.000000
84.	c.2502del	p.Arg835Alafs*2	frameshift	1	Pathogenic	0.000000
85.	c.1756C>G	p.P586A	missense	1	Likely Pathogenic	0.000000
86.	c.2603-2_2603-1delinsGA		essential splice site	1	Pathogenic	0.000000
87.	c.1999_2000delinsG	p.Leu667AspfsX15	frameshift	1	Pathogenic	0.000000
88.	c.1097A>C	p.Q366P	missense	1	VUS	0.000000
89.	c.1266_1267insTGAT	p.Ile423*	frameshift	1	Pathogenic	0.000000
90.	c.731del	p.Lys244Argfs*56	frameshift	1	Pathogenic	0.000000
91.	c.1457G>A	p.W486X	nonsense	1	Pathogenic	0.000000
92.	c.1377delC		frameshift	1	Pathogenic	0.000000
93.	c.1072G>A	p.D358N	missense	1	VUS	0.000008
94.	c.1A>T	p.Met1?	missense	1	Likely Pathogenic	0.000000
95.	c.3676C>T	p.R1226C	missense	1	VUS	0.000058
96.	c.821+2T>G		essential splice site	1	Pathogenic	0.000000
97.	c.3452C>T	p.A1151V	missense	1	VUS	0.000078
98.	c.1273C>T	p.Q425X	nonsense	1	Pathogenic	0.000000
99.	c.241G>T	p.V81F	missense	1	VUS	0.000000
100.	c.982delG		frameshift	1	Pathogenic	0.000000
101.	c.711C>A	p.Y237X	nonsense	1	Pathogenic	0.000000
102.	c.1090+1G>T		essential splice site	1	Pathogenic	0.000000
103.	c.821+1G>A		essential splice site	1	Pathogenic	0.000043
104.	c.373G>T	p.A125S	missense	1	VUS	0.000000
105.	c.3728C>G	p.P1243R	missense	1	VUS	0.000000
106.	c.631G>A	p.D211N	missense	1	VUS	0.000009
107.	c.49C>T	p.R17W	missense	1	VUS	0.000023
108.	c.2789del	p.Leu930Argfs*2	frameshift	1	Pathogenic	0.000000
109.	c.2504G>T	p.R835L	missense	1	Likely Pathogenic	0.000074
110.	c.2304_2308+2delCATCGGT		essential splice site	1	Pathogenic	0.000000
111.	c.3334_3351del	p.Trp1112_Glu1117del	inframe	1	Likely Pathogenic	0.000000
112.	c.2708G>A	p.G903D	missense	1	Likely Pathogenic	0.000000
113.	c.2030C>T	p.P677L	missense	1	VUS	0.000000
114.	c.2834G>A	p.R945Q	missense	1	VUS	0.000000
115.	c.2512dup	p.Glu838Glyfs*46	frameshift	1	Pathogenic	0.000000
116.	c.1523_1525delinsT	p.Gln508Leufs*22	frameshift	1	Pathogenic	0.000000
117.	c.1456T>G	p.W486G	missense	1	VUS	0.000000
118.	c.1174G>T	p.A392S	missense	1	VUS	0.000000
119.	c.2054_2067+11del	p.Lys685Argfs*3	frameshift	1	Pathogenic	0.000000
120.	c.1359del	p.Val454Cysfs*12	frameshift	1	Pathogenic	0.000000
121.	c.256_258del	p.Ser86del	inframe	1	VUS	0.000000
122.	c.1223+2T>C		essential splice site	1	Pathogenic	0.000000
123.	c.3617delG		frameshift	1	Pathogenic	0.000000
124.	c.611_618delinsT	p.Gly204Valfs*94	frameshift	1	Pathogenic	0.000000
125.	c.1303C>T	p.Q435X	nonsense	1	Pathogenic	0.000000
126.	c.100_110dup	p.Val38Serfs*5	frameshift	1	Pathogenic	0.000000
127.	c.1038_1042dupCGGCA		frameshift	1	Pathogenic	0.000008
128.	c.3490+1G>A		essential splice site	1	Pathogenic	0.000000
129.	c.1291G>A	p.D431N	missense	1	VUS	0.000028
130.	c.3373G>A	p.V1125M	missense	1	VUS	0.000022
131.	c.1021G>A	p.G341S	missense	1	VUS	0.000025
132.	c.146_148delTCA	p.Ile49del	inframe	1	VUS	0.000039
133.	c.799C>G	p.L267V	missense	1	VUS	0.000080
134.	c.459delC		frameshift	1	Pathogenic	0.000000
135.	c.3064C>T	p.R1022C	missense	1	VUS	0.000008
136.	c.187C>T	p.R63W	missense	1	VUS	0.000077
137.	c.3364A>T	p.T1122S	missense	1	Likely Pathogenic	0.000000
138.	c.2909G>A	p.R970Q	missense	1	Likely Pathogenic	0.000032
139.	c.3792_3793del	p.Cys1264*	frameshift	1	Likely Pathogenic	0.000000
140.	c.2534_2538delGCGTC		frameshift	1	Pathogenic	0.000000
141.	c.3256T>C	p.W1086R	missense	1	VUS	0.000000
142.	c.2449C>T	p.R817W	missense	1	VUS	0.000000
143.	c.2953A>G	p.K985E	missense	1	Pathogenic	0.000000
144.	c.2558delG		frameshift	1	Pathogenic	0.000000
145.	c.3297dup	p.Tyr1100Valfs*49	frameshift	1	Pathogenic	0.000000
146.	c.1841A>G	p.Y614C	missense	1	VUS	0.000000
147.	c.2149_2737del	p.Leu717Alafs*11	frameshift	1	Pathogenic	0.000000
148.	c.2197C>T	p.R733C	missense	1	Likely Pathogenic	0.000085
149.	c.2188del	p.Thr730Profs*24	frameshift	1	Pathogenic	0.000000
150.	c.1404del	p.Gln469Serfs*19	frameshift	1	Pathogenic	0.000000
151.	c.1790G>A	p.R597Q	missense	1	VUS	0.000000
152.	c.1731G>C	p.W577C	missense	1	VUS	0.000000
153.	c.1471G>A	p.V491M	missense	1	VUS	0.000058
154.	c.1351+1G>A		essential splice site	1	Pathogenic	0.000000
155.	c.1090+2T>C		essential splice site	1	Pathogenic	0.000000
156.	c.365C>A	p.A122D	missense	1	VUS	0.000000
157.	c.1231A>G	p.I411V	missense	1	VUS	0.000000
158.	c.701C>A	p.T234N	missense	1	Likely Pathogenic	0.000000
159.	c.1455A>T	p.K485N	missense	1	VUS	0.000000
160.	c.1037G>A	p.R346H	missense	1	VUS	0.000000
161.	c.3656T>C	p.L1219P	missense	1	VUS	0.000000
162.	c.1213A>G	p.M405V	missense	1	VUS	0.000000
163.	c.211_212delinsTA	p.Val71*	frameshift	1	Pathogenic	0.000000
164.	c.3257G>A	p.W1086X	nonsense	1	Pathogenic	0.000021
165.	c.532G>A	p.V178M	missense	1	VUS	0.000020
166.	c.1090+1G>A		essential splice site	1	Pathogenic	0.000000
167.	c.2953A>T	p.K985X	nonsense	1	Pathogenic	0.000000
168.	c.*26+2T>C		essential splice site	1	Likely Pathogenic	0.000000
169.	c.188G>A	p.R63Q	missense	1	VUS	0.000039
170.	c.3614G>C	p.R1205P	missense	1	Likely Pathogenic	0.000000
171.	c.3330+1G>C		essential splice site	1	Pathogenic	0.000000
172.	c.2748G>A	p.W916X	nonsense	1	Pathogenic	0.000000
173.	c.2873C>T	p.T958I	missense	1	VUS	0.000065
174.	c.3739G>A	p.D1247N	missense	1	VUS	0.000000
175.	c.2503C>T	p.R835C	missense	1	VUS	0.000024
176.	c.3043dup	p.Ala1015Glyfs*36	frameshift	1	Pathogenic	0.000000
177.	c.2603-1G>C		essential splice site	1	Pathogenic	0.000000
178.	c.2429_2503delins23	p.Arg810Profs*10	frameshift	1	Pathogenic	0.000000
179.	c.1797del	p.His599Glnfs*3	frameshift	1	Pathogenic	0.000000
180.	c.2690_2696del	p.Gly897Glufs*25	frameshift	1	Pathogenic	0.000000
181.	c.2247C>A	p.Y749X	nonsense	1	Pathogenic	0.000000
182.	c.1685C>T	p.A562V	missense	1	VUS	0.000008
183.	c.2265C>A	p.N755K	missense	1	Pathogenic	0.000000
184.	c.1352_1353del	p.Glu451Alafs*23	frameshift	1	Pathogenic	0.000000
185.	c.1458G>A	p.W486X	nonsense	1	Pathogenic	0.000000
186.	c.1433C>T	p.S478L	missense	1	Likely Pathogenic	0.000017
187.	c.3811C>T	p.R1271X	nonsense	1	VUS	0.000025
188.	c.1120C>T	p.Q374X	nonsense	1	Pathogenic	0.000000
189.	c.2065C>T	p.Q689X	nonsense	1	Pathogenic	0.000000
190.	c.255del	p.Ser86Profs*10	frameshift	1	Pathogenic	0.000000
191.	c.3614G>A	p.R1205Q	missense	1	VUS	0.000016
192.	c.553_562del	p.Lys185Trpfs*12	frameshift	1	Pathogenic	0.000000
193.	c.1021_1028del	p.Gly341*	frameshift	1	Pathogenic	0.000000
194.	c.994G>A	p.E332K	missense	1	VUS	0.000009
195.	c.743_746delACTG		frameshift	1	Pathogenic	0.000000
196.	c.3316G>A	p.D1106N	missense	1	VUS	0.000061
197.	c.1112C>T	p.P371L	missense	1	VUS	0.000028
198.	c.121dup	p.Arg41Profs*8	frameshift	1	Pathogenic	0.000000
199.	c.3572C>T	p.S1191L	missense	1	VUS	0.000016
200.	c.2995-1G>A		essential splice site	1	Pathogenic	0.000000
201.	c.148A>G	p.S50G	missense	1	VUS	0.000038
202.	c.772+1G>A		essential splice site	1	Pathogenic	0.000000
203.	c.3206C>A	p.P1069H	missense	1	Likely Pathogenic	0.000000
204.	c.3019T>C	p.W1007R	missense	1	VUS	0.000000
205.	c.3357C>A	p.Y1119X	nonsense	1	Pathogenic	0.000000
206.	c.2807dup	p.Ala938Glyfs*113	frameshift	1	Pathogenic	0.000000
207.	c.2371C>T	p.Q791X	nonsense	1	Pathogenic	0.000000
208.	c.2269G>A	p.V757M	missense	1	VUS	0.000066
209.	c.1828G>C	p.D610H	missense	1	VUS	0.000058
210.	c.2718_2719dup	p.Glu907Glyfs*18	frameshift	1	Pathogenic	0.000000
211.	c.1569dup	p.His524Alafs*7	frameshift	1	Pathogenic	0.000000
212.	c.1898-1G>A		essential splice site	1	Pathogenic	0.000000
213.	c.1201C>T	p.Q401X	nonsense	1	Pathogenic	0.000000
214.	c.2161_2168del	p.Thr721Profs*23	frameshift	1	Pathogenic	0.000000
215.	c.1591G>A	p.G531R	missense	1	Likely Pathogenic	0.000017
216.	c.1376_1377del	p.Pro459Leufs*15	frameshift	1	Pathogenic	0.000000
217.	c.2381C>A	p.P794Q	missense	1	VUS	0.000000
218.	c.1789C>T	p.R597W	missense	1	VUS	0.000038
219.	c.3624delC		frameshift	1	Pathogenic	0.000000
220.	c.655-2del		essential splice site	1	Pathogenic	0.000000
221.	c.3713T>C	p.L1238P	missense	1	Likely Pathogenic	0.000000
222.	c.1080G>C	p.K360N	missense	1	VUS	0.000000
223.	c.351_352del	p.Gly118Argfs*8	frameshift	1	Pathogenic	0.000000
224.	c.1224-1G>T		essential splice site	1	Pathogenic	0.000000
225.	c.844C>T	p.R282W	missense	1	Likely Pathogenic	0.000000
226.	c.3605delG		frameshift	1	Pathogenic	0.000000
227.	c.391dup	p.Ala131Glyfs*22	frameshift	1	Pathogenic	0.000000
228.	c.1021G>C	p.G341R	missense	1	VUS	0.000000
229.	c.1153G>A	p.V385M	missense	1	VUS	0.000010
230.	c.177dup	p.Glu60Argfs*53	frameshift	1	Pathogenic	0.000000
231.	c.811_817delTTCCGCC		frameshift	1	Pathogenic	0.000000
232.	c.3253G>T	p.E1085X	nonsense	1	Pathogenic	0.000000
233.	c.506-1G>A		essential splice site	1	Pathogenic	0.000000
234.	c.932C>A	p.S311X	nonsense	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.