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