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