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.3697C>T	p.Q1233X	nonsense	4	Likely Pathogenic	0.000008
30.	c.2556_2557delinsTCT	p.Gly853fs	frameshift	4	Pathogenic	0.000000
31.	c.1484G>A	p.R495Q	missense	4	Likely Pathogenic	0.000008
32.	c.484C>T	p.Q162X	nonsense	4	Pathogenic	0.000000
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.3277G>T	p.G1093C	missense	3	VUS	0.000020
43.	c.2545del	p.Val849Serfs*30	frameshift	3	Pathogenic	0.000000
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.2524dup	p.Tyr842Leufs*42	frameshift	2	Pathogenic	0.000000
51.	c.126G>A	p.W42X	nonsense	2	Pathogenic	0.000000
52.	c.2905+2dup		essential splice site	2	Likely Pathogenic	0.000000
53.	c.2300A>G	p.K767R	missense	2	VUS	0.000016
54.	c.1483C>T	p.R495W	missense	2	Likely Pathogenic	0.000000
55.	c.3271del	p.Asp1091Metfs*98	frameshift	2	Pathogenic	0.000000
56.	c.177_187del	p.Glu60AlafsX49	frameshift	2	Pathogenic	0.000000
57.	c.3455_3466del	p.Ala1152_Lys1155del	inframe	2	Likely Pathogenic	0.000000
58.	c.557C>T	p.P186L	missense	2	VUS	0.000047
59.	c.443dup	p.Ala149Serfs*4	frameshift	2	Pathogenic	0.000000
60.	c.2308+1G>A		essential splice site	2	Pathogenic	0.000000
61.	c.2219G>C	p.G740A	missense	2	VUS	0.000000
62.	c.747C>A	p.C249X	nonsense	2	Pathogenic	0.000000
63.	c.25+1G>A		essential splice site	2	Pathogenic	0.000000
64.	c.3751T>C	p.Y1251H	missense	2	VUS	0.000000
65.	c.3582_3593delGGGCTACACTGC		inframe	2	Likely Pathogenic	0.000000
66.	c.2526C>G	p.Y842X	nonsense	2	Pathogenic	0.000000
67.	c.1886T>C	p.L629P	missense	2	VUS	0.000000
68.	c.833delG	p.Gly278GlufsX22	frameshift	2	Pathogenic	0.000000
69.	c.2573G>A	p.S858N	missense	2	Likely Pathogenic	0.000000
70.	c.818G>A	p.R273H	missense	2	VUS	0.000042
71.	c.3470C>T	p.P1157L	missense	2	VUS	0.000093
72.	c.2905C>T	p.Q969X	nonsense	2	Pathogenic	0.000000
73.	c.1828G>A	p.D610N	missense	2	VUS	0.000000
74.	c.2432A>G	p.K811R	missense	2	VUS	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.1174G>T	p.A392S	missense	1	VUS	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.3713T>C	p.L1238P	missense	1	Likely Pathogenic	0.000000
85.	c.100_110dup	p.Val38Serfs*5	frameshift	1	Pathogenic	0.000000
86.	c.1038_1042dupCGGCA		frameshift	1	Pathogenic	0.000008
87.	c.2807dup	p.Ala938Glyfs*113	frameshift	1	Pathogenic	0.000000
88.	c.256_258del	p.Ser86del	inframe	1	VUS	0.000000
89.	c.3206C>A	p.P1069H	missense	1	Likely Pathogenic	0.000000
90.	c.3605delG		frameshift	1	Pathogenic	0.000000
91.	c.611_618delinsT	p.Gly204Valfs*94	frameshift	1	Pathogenic	0.000000
92.	c.3357C>A	p.Y1119X	nonsense	1	Pathogenic	0.000000
93.	c.2534_2538delGCGTC		frameshift	1	Pathogenic	0.000000
94.	c.3064C>T	p.R1022C	missense	1	VUS	0.000008
95.	c.2718_2719dup	p.Glu907Glyfs*18	frameshift	1	Pathogenic	0.000000
96.	c.2371C>T	p.Q791X	nonsense	1	Pathogenic	0.000000
97.	c.2909G>A	p.R970Q	missense	1	Likely Pathogenic	0.000032
98.	c.1841A>G	p.Y614C	missense	1	VUS	0.000000
99.	c.1376_1377del	p.Pro459Leufs*15	frameshift	1	Pathogenic	0.000000
100.	c.2449C>T	p.R817W	missense	1	VUS	0.000000
101.	c.2381C>A	p.P794Q	missense	1	VUS	0.000000
102.	c.2197C>T	p.R733C	missense	1	Likely Pathogenic	0.000085
103.	c.1569dup	p.His524Alafs*7	frameshift	1	Pathogenic	0.000000
104.	c.2558delG		frameshift	1	Pathogenic	0.000000
105.	c.2161_2168del	p.Thr721Profs*23	frameshift	1	Pathogenic	0.000000
106.	c.1790G>A	p.R597Q	missense	1	VUS	0.000000
107.	c.1224-1G>T		essential splice site	1	Pathogenic	0.000000
108.	c.1471G>A	p.V491M	missense	1	VUS	0.000058
109.	c.1021G>C	p.G341R	missense	1	VUS	0.000000
110.	c.1153G>A	p.V385M	missense	1	VUS	0.000010
111.	c.844C>T	p.R282W	missense	1	Likely Pathogenic	0.000000
112.	c.1351+1G>A		essential splice site	1	Pathogenic	0.000000
113.	c.506-1G>A		essential splice site	1	Pathogenic	0.000000
114.	c.932C>A	p.S311X	nonsense	1	Pathogenic	0.000000
115.	c.811_817delTTCCGCC		frameshift	1	Pathogenic	0.000000
116.	c.365C>A	p.A122D	missense	1	VUS	0.000000
117.	c.701C>A	p.T234N	missense	1	Likely Pathogenic	0.000000
118.	c.3257G>A	p.W1086X	nonsense	1	Pathogenic	0.000021
119.	c.3676C>T	p.R1226C	missense	1	VUS	0.000058
120.	c.1090+2T>C		essential splice site	1	Pathogenic	0.000000
121.	c.3452C>T	p.A1151V	missense	1	VUS	0.000078
122.	c.211_212delinsTA	p.Val71*	frameshift	1	Pathogenic	0.000000
123.	c.2953A>T	p.K985X	nonsense	1	Pathogenic	0.000000
124.	c.2968C>G	p.P990A	missense	1	Likely Pathogenic	0.000000
125.	c.2584C>T	p.Q862X	nonsense	1	Pathogenic	0.000000
126.	c.3316del	p.Asp1106Thrfs*83	frameshift	1	Pathogenic	0.000000
127.	c.2738-2A>G		essential splice site	1	Pathogenic	0.000000
128.	c.1756C>G	p.P586A	missense	1	Likely Pathogenic	0.000000
129.	c.2603-2_2603-1delinsGA		essential splice site	1	Pathogenic	0.000000
130.	c.2873C>T	p.T958I	missense	1	VUS	0.000065
131.	c.1405C>T	p.Q469X	nonsense	1	Pathogenic	0.000000
132.	c.2503C>T	p.R835C	missense	1	VUS	0.000024
133.	c.2502del	p.Arg835Alafs*2	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.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.1273C>T	p.Q425X	nonsense	1	Pathogenic	0.000000
141.	c.1090+1G>T		essential splice site	1	Pathogenic	0.000000
142.	c.821+1G>A		essential splice site	1	Pathogenic	0.000043
143.	c.982delG		frameshift	1	Pathogenic	0.000000
144.	c.711C>A	p.Y237X	nonsense	1	Pathogenic	0.000000
145.	c.3728C>G	p.P1243R	missense	1	VUS	0.000000
146.	c.631G>A	p.D211N	missense	1	VUS	0.000009
147.	c.1120C>T	p.Q374X	nonsense	1	Pathogenic	0.000000
148.	c.3490+1G>A		essential splice site	1	Pathogenic	0.000000
149.	c.49C>T	p.R17W	missense	1	VUS	0.000023
150.	c.3617delG		frameshift	1	Pathogenic	0.000000
151.	c.373G>T	p.A125S	missense	1	VUS	0.000000
152.	c.553_562del	p.Lys185Trpfs*12	frameshift	1	Pathogenic	0.000000
153.	c.3334_3351del	p.Trp1112_Glu1117del	inframe	1	Likely Pathogenic	0.000000
154.	c.1021_1028del	p.Gly341*	frameshift	1	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.255del	p.Ser86Profs*10	frameshift	1	Pathogenic	0.000000
158.	c.2995-1G>A		essential splice site	1	Pathogenic	0.000000
159.	c.2834G>A	p.R945Q	missense	1	VUS	0.000000
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.121dup	p.Arg41Profs*8	frameshift	1	Pathogenic	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.1591G>A	p.G531R	missense	1	Likely Pathogenic	0.000017
170.	c.1291G>A	p.D431N	missense	1	VUS	0.000028
171.	c.1789C>T	p.R597W	missense	1	VUS	0.000038
172.	c.1223+2T>C		essential splice site	1	Pathogenic	0.000000
173.	c.1898-1G>A		essential splice site	1	Pathogenic	0.000000
174.	c.1021G>A	p.G341S	missense	1	VUS	0.000025
175.	c.799C>G	p.L267V	missense	1	VUS	0.000080
176.	c.459delC		frameshift	1	Pathogenic	0.000000
177.	c.1201C>T	p.Q401X	nonsense	1	Pathogenic	0.000000
178.	c.146_148delTCA	p.Ile49del	inframe	1	VUS	0.000039
179.	c.1080G>C	p.K360N	missense	1	VUS	0.000000
180.	c.3792_3793del	p.Cys1264*	frameshift	1	Likely Pathogenic	0.000000
181.	c.351_352del	p.Gly118Argfs*8	frameshift	1	Pathogenic	0.000000
182.	c.3256T>C	p.W1086R	missense	1	VUS	0.000000
183.	c.187C>T	p.R63W	missense	1	VUS	0.000077
184.	c.655-2del		essential splice site	1	Pathogenic	0.000000
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.3656T>C	p.L1219P	missense	1	VUS	0.000000
188.	c.2149_2737del	p.Leu717Alafs*11	frameshift	1	Pathogenic	0.000000
189.	c.177dup	p.Glu60Argfs*53	frameshift	1	Pathogenic	0.000000
190.	c.2953A>G	p.K985E	missense	1	Pathogenic	0.000000
191.	c.391dup	p.Ala131Glyfs*22	frameshift	1	Pathogenic	0.000000
192.	c.3297dup	p.Tyr1100Valfs*49	frameshift	1	Pathogenic	0.000000
193.	c.2198G>A	p.R733H	missense	1	VUS	0.000034
194.	c.1731G>C	p.W577C	missense	1	VUS	0.000000
195.	c.2188del	p.Thr730Profs*24	frameshift	1	Pathogenic	0.000000
196.	c.1404del	p.Gln469Serfs*19	frameshift	1	Pathogenic	0.000000
197.	c.1231A>G	p.I411V	missense	1	VUS	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.2249C>T	p.T750M	missense	1	Likely Pathogenic	0.000024
202.	c.1213A>G	p.M405V	missense	1	VUS	0.000000
203.	c.1377delC		frameshift	1	Pathogenic	0.000000
204.	c.1037G>A	p.R346H	missense	1	VUS	0.000000
205.	c.3811C>T	p.R1271X	nonsense	1	VUS	0.000025
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.731del	p.Lys244Argfs*56	frameshift	1	Pathogenic	0.000000
210.	c.3614G>C	p.R1205P	missense	1	Likely Pathogenic	0.000000
211.	c.1097A>C	p.Q366P	missense	1	VUS	0.000000
212.	c.*26+2T>C		essential splice site	1	Likely Pathogenic	0.000000
213.	c.3614G>A	p.R1205Q	missense	1	VUS	0.000016
214.	c.3043dup	p.Ala1015Glyfs*36	frameshift	1	Pathogenic	0.000000
215.	c.3572C>T	p.S1191L	missense	1	VUS	0.000016
216.	c.2603-1G>C		essential splice site	1	Pathogenic	0.000000
217.	c.3330+1G>C		essential splice site	1	Pathogenic	0.000000
218.	c.1A>T	p.Met1?	missense	1	Likely Pathogenic	0.000000
219.	c.821+2T>G		essential splice site	1	Pathogenic	0.000000
220.	c.2748G>A	p.W916X	nonsense	1	Pathogenic	0.000000
221.	c.3316G>A	p.D1106N	missense	1	VUS	0.000061
222.	c.3739G>A	p.D1247N	missense	1	VUS	0.000000
223.	c.241G>T	p.V81F	missense	1	VUS	0.000000
224.	c.2304_2308+2delCATCGGT		essential splice site	1	Pathogenic	0.000000
225.	c.2247C>A	p.Y749X	nonsense	1	Pathogenic	0.000000
226.	c.2504G>T	p.R835L	missense	1	Likely Pathogenic	0.000074
227.	c.2429_2503delins23	p.Arg810Profs*10	frameshift	1	Pathogenic	0.000000
228.	c.1797del	p.His599Glnfs*3	frameshift	1	Pathogenic	0.000000
229.	c.2690_2696del	p.Gly897Glufs*25	frameshift	1	Pathogenic	0.000000
230.	c.2065C>T	p.Q689X	nonsense	1	Pathogenic	0.000000
231.	c.1352_1353del	p.Glu451Alafs*23	frameshift	1	Pathogenic	0.000000
232.	c.2030C>T	p.P677L	missense	1	VUS	0.000000
233.	c.1458G>A	p.W486X	nonsense	1	Pathogenic	0.000000
234.	c.1456T>G	p.W486G	missense	1	VUS	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.