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.2429G>A	p.R810H	missense	11	VUS	0.000033
9.	c.2827C>T	p.R943X	nonsense	11	Pathogenic	0.000017
10.	c.1483C>G	p.R495G	missense	10	Likely Pathogenic	0.000000
11.	c.1928-2A>G		essential splice site	10	Pathogenic	0.000000
12.	c.3613C>T	p.R1205W	missense	10	Likely Pathogenic	0.000016
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.2864_2865delCT		frameshift	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.2556_2557delinsTCT	p.Gly853fs	frameshift	4	Pathogenic	0.000000
26.	c.1484G>A	p.R495Q	missense	4	Likely Pathogenic	0.000008
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.3798C>G	p.C1266W	missense	4	VUS	0.000000
30.	c.3163A>T	p.K1055X	nonsense	4	Pathogenic	0.000000
31.	c.484C>T	p.Q162X	nonsense	4	Pathogenic	0.000000
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.2905+1G>A		essential splice site	3	Pathogenic	0.000000
35.	c.1123G>A	p.V375M	missense	3	VUS	0.000009
36.	c.3763G>A	p.A1255T	missense	3	VUS	0.000075
37.	c.3408C>A	p.Y1136X	nonsense	3	Pathogenic	0.000000
38.	c.3600_3609delCTGCTGTGCT		frameshift	3	Pathogenic	0.000000
39.	c.2545del	p.Val849Serfs*30	frameshift	3	Pathogenic	0.000000
40.	c.3277G>T	p.G1093C	missense	3	VUS	0.000020
41.	c.710A>C	p.Y237S	missense	3	Likely Pathogenic	0.000000
42.	c.3181C>T	p.Q1061X	nonsense	3	Pathogenic	0.000016
43.	c.1720C>T	p.R574W	missense	3	VUS	0.000054
44.	c.3286G>T	p.E1096X	nonsense	3	Pathogenic	0.000000
45.	c.2210C>T	p.T737M	missense	3	VUS	0.000050
46.	c.3129C>A	p.Y1043X	nonsense	3	Pathogenic	0.000000
47.	c.1886T>C	p.L629P	missense	2	VUS	0.000000
48.	c.2526C>G	p.Y842X	nonsense	2	Pathogenic	0.000000
49.	c.126G>A	p.W42X	nonsense	2	Pathogenic	0.000000
50.	c.833delG	p.Gly278GlufsX22	frameshift	2	Pathogenic	0.000000
51.	c.2573G>A	p.S858N	missense	2	Likely Pathogenic	0.000000
52.	c.443dup	p.Ala149Serfs*4	frameshift	2	Pathogenic	0.000000
53.	c.818G>A	p.R273H	missense	2	VUS	0.000042
54.	c.3470C>T	p.P1157L	missense	2	VUS	0.000093
55.	c.2905C>T	p.Q969X	nonsense	2	Pathogenic	0.000000
56.	c.1828G>A	p.D610N	missense	2	VUS	0.000000
57.	c.2432A>G	p.K811R	missense	2	VUS	0.000000
58.	c.747C>A	p.C249X	nonsense	2	Pathogenic	0.000000
59.	c.25+1G>A		essential splice site	2	Pathogenic	0.000000
60.	c.1505G>A	p.R502Q	missense	2	Pathogenic	0.000000
61.	c.3005G>A	p.R1002Q	missense	2	VUS	0.000046
62.	c.3627+1G>T		essential splice site	2	Pathogenic	0.000000
63.	c.3752A>G	p.Y1251C	missense	2	VUS	0.000000
64.	c.2905+2dup		essential splice site	2	Likely Pathogenic	0.000000
65.	c.2524dup	p.Tyr842Leufs*42	frameshift	2	Pathogenic	0.000000
66.	c.2300A>G	p.K767R	missense	2	VUS	0.000016
67.	c.1483C>T	p.R495W	missense	2	Likely Pathogenic	0.000000
68.	c.557C>T	p.P186L	missense	2	VUS	0.000047
69.	c.3271del	p.Asp1091Metfs*98	frameshift	2	Pathogenic	0.000000
70.	c.177_187del	p.Glu60AlafsX49	frameshift	2	Pathogenic	0.000000
71.	c.3455_3466del	p.Ala1152_Lys1155del	inframe	2	Likely Pathogenic	0.000000
72.	c.2308+1G>A		essential splice site	2	Pathogenic	0.000000
73.	c.2219G>C	p.G740A	missense	2	VUS	0.000000
74.	c.3751T>C	p.Y1251H	missense	2	VUS	0.000000
75.	c.3582_3593delGGGCTACACTGC		inframe	2	Likely Pathogenic	0.000000
76.	c.2708G>A	p.G903D	missense	1	Likely Pathogenic	0.000000
77.	c.2834G>A	p.R945Q	missense	1	VUS	0.000000
78.	c.2512dup	p.Glu838Glyfs*46	frameshift	1	Pathogenic	0.000000
79.	c.3019T>C	p.W1007R	missense	1	VUS	0.000000
80.	c.1523_1525delinsT	p.Gln508Leufs*22	frameshift	1	Pathogenic	0.000000
81.	c.1174G>T	p.A392S	missense	1	VUS	0.000000
82.	c.2269G>A	p.V757M	missense	1	VUS	0.000066
83.	c.2054_2067+11del	p.Lys685Argfs*3	frameshift	1	Pathogenic	0.000000
84.	c.1828G>C	p.D610H	missense	1	VUS	0.000058
85.	c.1359del	p.Val454Cysfs*12	frameshift	1	Pathogenic	0.000000
86.	c.611_618delinsT	p.Gly204Valfs*94	frameshift	1	Pathogenic	0.000000
87.	c.1898-1G>A		essential splice site	1	Pathogenic	0.000000
88.	c.100_110dup	p.Val38Serfs*5	frameshift	1	Pathogenic	0.000000
89.	c.1591G>A	p.G531R	missense	1	Likely Pathogenic	0.000017
90.	c.1038_1042dupCGGCA		frameshift	1	Pathogenic	0.000008
91.	c.1291G>A	p.D431N	missense	1	VUS	0.000028
92.	c.256_258del	p.Ser86del	inframe	1	VUS	0.000000
93.	c.1789C>T	p.R597W	missense	1	VUS	0.000038
94.	c.1223+2T>C		essential splice site	1	Pathogenic	0.000000
95.	c.1021G>A	p.G341S	missense	1	VUS	0.000025
96.	c.146_148delTCA	p.Ile49del	inframe	1	VUS	0.000039
97.	c.799C>G	p.L267V	missense	1	VUS	0.000080
98.	c.459delC		frameshift	1	Pathogenic	0.000000
99.	c.3253G>T	p.E1085X	nonsense	1	Pathogenic	0.000000
100.	c.3364A>T	p.T1122S	missense	1	Likely Pathogenic	0.000000
101.	c.3656T>C	p.L1219P	missense	1	VUS	0.000000
102.	c.3792_3793del	p.Cys1264*	frameshift	1	Likely Pathogenic	0.000000
103.	c.3256T>C	p.W1086R	missense	1	VUS	0.000000
104.	c.187C>T	p.R63W	missense	1	VUS	0.000077
105.	c.2953A>G	p.K985E	missense	1	Pathogenic	0.000000
106.	c.3297dup	p.Tyr1100Valfs*49	frameshift	1	Pathogenic	0.000000
107.	c.2149_2737del	p.Leu717Alafs*11	frameshift	1	Pathogenic	0.000000
108.	c.2188del	p.Thr730Profs*24	frameshift	1	Pathogenic	0.000000
109.	c.1404del	p.Gln469Serfs*19	frameshift	1	Pathogenic	0.000000
110.	c.2198G>A	p.R733H	missense	1	VUS	0.000034
111.	c.1731G>C	p.W577C	missense	1	VUS	0.000000
112.	c.1624+1G>A		essential splice site	1	Pathogenic	0.000000
113.	c.1090+2T>C		essential splice site	1	Pathogenic	0.000000
114.	c.2249C>T	p.T750M	missense	1	Likely Pathogenic	0.000024
115.	c.365C>A	p.A122D	missense	1	VUS	0.000000
116.	c.1231A>G	p.I411V	missense	1	VUS	0.000000
117.	c.701C>A	p.T234N	missense	1	Likely Pathogenic	0.000000
118.	c.1999_2000delinsG	p.Leu667AspfsX15	frameshift	1	Pathogenic	0.000000
119.	c.1455A>T	p.K485N	missense	1	VUS	0.000000
120.	c.1037G>A	p.R346H	missense	1	VUS	0.000000
121.	c.1213A>G	p.M405V	missense	1	VUS	0.000000
122.	c.211_212delinsTA	p.Val71*	frameshift	1	Pathogenic	0.000000
123.	c.1377delC		frameshift	1	Pathogenic	0.000000
124.	c.532G>A	p.V178M	missense	1	VUS	0.000020
125.	c.3811C>T	p.R1271X	nonsense	1	VUS	0.000025
126.	c.1090+1G>A		essential splice site	1	Pathogenic	0.000000
127.	c.*26+2T>C		essential splice site	1	Likely Pathogenic	0.000000
128.	c.3614G>A	p.R1205Q	missense	1	VUS	0.000016
129.	c.188G>A	p.R63Q	missense	1	VUS	0.000039
130.	c.3614G>C	p.R1205P	missense	1	Likely Pathogenic	0.000000
131.	c.2748G>A	p.W916X	nonsense	1	Pathogenic	0.000000
132.	c.3316G>A	p.D1106N	missense	1	VUS	0.000061
133.	c.3739G>A	p.D1247N	missense	1	VUS	0.000000
134.	c.3043dup	p.Ala1015Glyfs*36	frameshift	1	Pathogenic	0.000000
135.	c.3572C>T	p.S1191L	missense	1	VUS	0.000016
136.	c.2603-1G>C		essential splice site	1	Pathogenic	0.000000
137.	c.3330+1G>C		essential splice site	1	Pathogenic	0.000000
138.	c.1797del	p.His599Glnfs*3	frameshift	1	Pathogenic	0.000000
139.	c.2690_2696del	p.Gly897Glufs*25	frameshift	1	Pathogenic	0.000000
140.	c.2304_2308+2delCATCGGT		essential splice site	1	Pathogenic	0.000000
141.	c.2247C>A	p.Y749X	nonsense	1	Pathogenic	0.000000
142.	c.2504G>T	p.R835L	missense	1	Likely Pathogenic	0.000074
143.	c.2429_2503delins23	p.Arg810Profs*10	frameshift	1	Pathogenic	0.000000
144.	c.1352_1353del	p.Glu451Alafs*23	frameshift	1	Pathogenic	0.000000
145.	c.2030C>T	p.P677L	missense	1	VUS	0.000000
146.	c.1458G>A	p.W486X	nonsense	1	Pathogenic	0.000000
147.	c.1120C>T	p.Q374X	nonsense	1	Pathogenic	0.000000
148.	c.2065C>T	p.Q689X	nonsense	1	Pathogenic	0.000000
149.	c.255del	p.Ser86Profs*10	frameshift	1	Pathogenic	0.000000
150.	c.1456T>G	p.W486G	missense	1	VUS	0.000000
151.	c.553_562del	p.Lys185Trpfs*12	frameshift	1	Pathogenic	0.000000
152.	c.1021_1028del	p.Gly341*	frameshift	1	Pathogenic	0.000000
153.	c.743_746delACTG		frameshift	1	Pathogenic	0.000000
154.	c.1112C>T	p.P371L	missense	1	VUS	0.000028
155.	c.121dup	p.Arg41Profs*8	frameshift	1	Pathogenic	0.000000
156.	c.1303C>T	p.Q435X	nonsense	1	Pathogenic	0.000000
157.	c.994G>A	p.E332K	missense	1	VUS	0.000009
158.	c.3713T>C	p.L1238P	missense	1	Likely Pathogenic	0.000000
159.	c.148A>G	p.S50G	missense	1	VUS	0.000038
160.	c.772+1G>A		essential splice site	1	Pathogenic	0.000000
161.	c.3624delC		frameshift	1	Pathogenic	0.000000
162.	c.3206C>A	p.P1069H	missense	1	Likely Pathogenic	0.000000
163.	c.3605delG		frameshift	1	Pathogenic	0.000000
164.	c.3357C>A	p.Y1119X	nonsense	1	Pathogenic	0.000000
165.	c.2807dup	p.Ala938Glyfs*113	frameshift	1	Pathogenic	0.000000
166.	c.2371C>T	p.Q791X	nonsense	1	Pathogenic	0.000000
167.	c.2909G>A	p.R970Q	missense	1	Likely Pathogenic	0.000032
168.	c.2534_2538delGCGTC		frameshift	1	Pathogenic	0.000000
169.	c.3064C>T	p.R1022C	missense	1	VUS	0.000008
170.	c.2718_2719dup	p.Glu907Glyfs*18	frameshift	1	Pathogenic	0.000000
171.	c.1201C>T	p.Q401X	nonsense	1	Pathogenic	0.000000
172.	c.2161_2168del	p.Thr721Profs*23	frameshift	1	Pathogenic	0.000000
173.	c.1841A>G	p.Y614C	missense	1	VUS	0.000000
174.	c.1376_1377del	p.Pro459Leufs*15	frameshift	1	Pathogenic	0.000000
175.	c.2449C>T	p.R817W	missense	1	VUS	0.000000
176.	c.2381C>A	p.P794Q	missense	1	VUS	0.000000
177.	c.2197C>T	p.R733C	missense	1	Likely Pathogenic	0.000085
178.	c.1569dup	p.His524Alafs*7	frameshift	1	Pathogenic	0.000000
179.	c.2558delG		frameshift	1	Pathogenic	0.000000
180.	c.1471G>A	p.V491M	missense	1	VUS	0.000058
181.	c.655-2del		essential splice site	1	Pathogenic	0.000000
182.	c.1080G>C	p.K360N	missense	1	VUS	0.000000
183.	c.351_352del	p.Gly118Argfs*8	frameshift	1	Pathogenic	0.000000
184.	c.1790G>A	p.R597Q	missense	1	VUS	0.000000
185.	c.1224-1G>T		essential splice site	1	Pathogenic	0.000000
186.	c.844C>T	p.R282W	missense	1	Likely Pathogenic	0.000000
187.	c.1351+1G>A		essential splice site	1	Pathogenic	0.000000
188.	c.391dup	p.Ala131Glyfs*22	frameshift	1	Pathogenic	0.000000
189.	c.1021G>C	p.G341R	missense	1	VUS	0.000000
190.	c.1153G>A	p.V385M	missense	1	VUS	0.000010
191.	c.177dup	p.Glu60Argfs*53	frameshift	1	Pathogenic	0.000000
192.	c.811_817delTTCCGCC		frameshift	1	Pathogenic	0.000000
193.	c.506-1G>A		essential splice site	1	Pathogenic	0.000000
194.	c.932C>A	p.S311X	nonsense	1	Pathogenic	0.000000
195.	c.3676C>T	p.R1226C	missense	1	VUS	0.000058
196.	c.3452C>T	p.A1151V	missense	1	VUS	0.000078
197.	c.3257G>A	p.W1086X	nonsense	1	Pathogenic	0.000021
198.	c.2584C>T	p.Q862X	nonsense	1	Pathogenic	0.000000
199.	c.3316del	p.Asp1106Thrfs*83	frameshift	1	Pathogenic	0.000000
200.	c.2738-2A>G		essential splice site	1	Pathogenic	0.000000
201.	c.2953A>T	p.K985X	nonsense	1	Pathogenic	0.000000
202.	c.2968C>G	p.P990A	missense	1	Likely Pathogenic	0.000000
203.	c.1405C>T	p.Q469X	nonsense	1	Pathogenic	0.000000
204.	c.2503C>T	p.R835C	missense	1	VUS	0.000024
205.	c.2502del	p.Arg835Alafs*2	frameshift	1	Pathogenic	0.000000
206.	c.1756C>G	p.P586A	missense	1	Likely Pathogenic	0.000000
207.	c.2603-2_2603-1delinsGA		essential splice site	1	Pathogenic	0.000000
208.	c.2873C>T	p.T958I	missense	1	VUS	0.000065
209.	c.1266_1267insTGAT	p.Ile423*	frameshift	1	Pathogenic	0.000000
210.	c.731del	p.Lys244Argfs*56	frameshift	1	Pathogenic	0.000000
211.	c.1457G>A	p.W486X	nonsense	1	Pathogenic	0.000000
212.	c.1685C>T	p.A562V	missense	1	VUS	0.000008
213.	c.1097A>C	p.Q366P	missense	1	VUS	0.000000
214.	c.2265C>A	p.N755K	missense	1	Pathogenic	0.000000
215.	c.1A>T	p.Met1?	missense	1	Likely Pathogenic	0.000000
216.	c.821+2T>G		essential splice site	1	Pathogenic	0.000000
217.	c.1273C>T	p.Q425X	nonsense	1	Pathogenic	0.000000
218.	c.241G>T	p.V81F	missense	1	VUS	0.000000
219.	c.1433C>T	p.S478L	missense	1	Likely Pathogenic	0.000017
220.	c.1072G>A	p.D358N	missense	1	VUS	0.000008
221.	c.982delG		frameshift	1	Pathogenic	0.000000
222.	c.711C>A	p.Y237X	nonsense	1	Pathogenic	0.000000
223.	c.1090+1G>T		essential splice site	1	Pathogenic	0.000000
224.	c.821+1G>A		essential splice site	1	Pathogenic	0.000043
225.	c.3617delG		frameshift	1	Pathogenic	0.000000
226.	c.373G>T	p.A125S	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.3490+1G>A		essential splice site	1	Pathogenic	0.000000
230.	c.49C>T	p.R17W	missense	1	VUS	0.000023
231.	c.2995-1G>A		essential splice site	1	Pathogenic	0.000000
232.	c.3334_3351del	p.Trp1112_Glu1117del	inframe	1	Likely Pathogenic	0.000000
233.	c.2789del	p.Leu930Argfs*2	frameshift	1	Pathogenic	0.000000
234.	c.3373G>A	p.V1125M	missense	1	VUS	0.000022

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.