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