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.3613C>T	p.R1205W	missense	10	Likely Pathogenic	0.000016
11.	c.1483C>G	p.R495G	missense	10	Likely Pathogenic	0.000000
12.	c.1928-2A>G		essential splice site	10	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.2459G>A	p.R820Q	missense	5	VUS	0.000016
21.	c.2308G>A	p.D770N	missense	5	Likely Pathogenic	0.000008
22.	c.3065G>C	p.R1022P	missense	5	Likely Pathogenic	0.000025
23.	c.2267delC		frameshift	5	Pathogenic	0.000000
24.	c.2610delC		frameshift	5	Pathogenic	0.000000
25.	c.3798C>G	p.C1266W	missense	4	VUS	0.000000
26.	c.2556_2557delinsTCT	p.Gly853fs	frameshift	4	Pathogenic	0.000000
27.	c.3697C>T	p.Q1233X	nonsense	4	Likely Pathogenic	0.000008
28.	c.1484G>A	p.R495Q	missense	4	Likely Pathogenic	0.000008
29.	c.484C>T	p.Q162X	nonsense	4	Pathogenic	0.000000
30.	c.3163A>T	p.K1055X	nonsense	4	Pathogenic	0.000000
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.2905+1G>A		essential splice site	3	Pathogenic	0.000000
34.	c.1123G>A	p.V375M	missense	3	VUS	0.000009
35.	c.3181C>T	p.Q1061X	nonsense	3	Pathogenic	0.000016
36.	c.3286G>T	p.E1096X	nonsense	3	Pathogenic	0.000000
37.	c.3763G>A	p.A1255T	missense	3	VUS	0.000075
38.	c.1720C>T	p.R574W	missense	3	VUS	0.000054
39.	c.3129C>A	p.Y1043X	nonsense	3	Pathogenic	0.000000
40.	c.3600_3609delCTGCTGTGCT		frameshift	3	Pathogenic	0.000000
41.	c.710A>C	p.Y237S	missense	3	Likely Pathogenic	0.000000
42.	c.2309-1G>A		essential splice site	3	Pathogenic	0.000000
43.	c.3408C>A	p.Y1136X	nonsense	3	Pathogenic	0.000000
44.	c.2545del	p.Val849Serfs*30	frameshift	3	Pathogenic	0.000000
45.	c.3277G>T	p.G1093C	missense	3	VUS	0.000020
46.	c.2210C>T	p.T737M	missense	3	VUS	0.000050
47.	c.2526C>G	p.Y842X	nonsense	2	Pathogenic	0.000000
48.	c.3470C>T	p.P1157L	missense	2	VUS	0.000093
49.	c.3627+1G>T		essential splice site	2	Pathogenic	0.000000
50.	c.177_187del	p.Glu60AlafsX49	frameshift	2	Pathogenic	0.000000
51.	c.747C>A	p.C249X	nonsense	2	Pathogenic	0.000000
52.	c.3455_3466del	p.Ala1152_Lys1155del	inframe	2	Likely Pathogenic	0.000000
53.	c.557C>T	p.P186L	missense	2	VUS	0.000047
54.	c.25+1G>A		essential splice site	2	Pathogenic	0.000000
55.	c.2905+2dup		essential splice site	2	Likely Pathogenic	0.000000
56.	c.2524dup	p.Tyr842Leufs*42	frameshift	2	Pathogenic	0.000000
57.	c.3751T>C	p.Y1251H	missense	2	VUS	0.000000
58.	c.2905C>T	p.Q969X	nonsense	2	Pathogenic	0.000000
59.	c.3271del	p.Asp1091Metfs*98	frameshift	2	Pathogenic	0.000000
60.	c.2432A>G	p.K811R	missense	2	VUS	0.000000
61.	c.3582_3593delGGGCTACACTGC		inframe	2	Likely Pathogenic	0.000000
62.	c.833delG	p.Gly278GlufsX22	frameshift	2	Pathogenic	0.000000
63.	c.2219G>C	p.G740A	missense	2	VUS	0.000000
64.	c.3005G>A	p.R1002Q	missense	2	VUS	0.000046
65.	c.1828G>A	p.D610N	missense	2	VUS	0.000000
66.	c.2300A>G	p.K767R	missense	2	VUS	0.000016
67.	c.2573G>A	p.S858N	missense	2	Likely Pathogenic	0.000000
68.	c.1505G>A	p.R502Q	missense	2	Pathogenic	0.000000
69.	c.818G>A	p.R273H	missense	2	VUS	0.000042
70.	c.1886T>C	p.L629P	missense	2	VUS	0.000000
71.	c.126G>A	p.W42X	nonsense	2	Pathogenic	0.000000
72.	c.2308+1G>A		essential splice site	2	Pathogenic	0.000000
73.	c.1483C>T	p.R495W	missense	2	Likely Pathogenic	0.000000
74.	c.3752A>G	p.Y1251C	missense	2	VUS	0.000000
75.	c.443dup	p.Ala149Serfs*4	frameshift	2	Pathogenic	0.000000
76.	c.2269G>A	p.V757M	missense	1	VUS	0.000066
77.	c.3713T>C	p.L1238P	missense	1	Likely Pathogenic	0.000000
78.	c.1685C>T	p.A562V	missense	1	VUS	0.000008
79.	c.3624delC		frameshift	1	Pathogenic	0.000000
80.	c.3605delG		frameshift	1	Pathogenic	0.000000
81.	c.2748G>A	p.W916X	nonsense	1	Pathogenic	0.000000
82.	c.1273C>T	p.Q425X	nonsense	1	Pathogenic	0.000000
83.	c.3316G>A	p.D1106N	missense	1	VUS	0.000061
84.	c.3043dup	p.Ala1015Glyfs*36	frameshift	1	Pathogenic	0.000000
85.	c.1433C>T	p.S478L	missense	1	Likely Pathogenic	0.000017
86.	c.2558delG		frameshift	1	Pathogenic	0.000000
87.	c.3019T>C	p.W1007R	missense	1	VUS	0.000000
88.	c.844C>T	p.R282W	missense	1	Likely Pathogenic	0.000000
89.	c.2603-1G>C		essential splice site	1	Pathogenic	0.000000
90.	c.1072G>A	p.D358N	missense	1	VUS	0.000008
91.	c.506-1G>A		essential splice site	1	Pathogenic	0.000000
92.	c.1797del	p.His599Glnfs*3	frameshift	1	Pathogenic	0.000000
93.	c.2690_2696del	p.Gly897Glufs*25	frameshift	1	Pathogenic	0.000000
94.	c.1090+1G>T		essential splice site	1	Pathogenic	0.000000
95.	c.2247C>A	p.Y749X	nonsense	1	Pathogenic	0.000000
96.	c.811_817delTTCCGCC		frameshift	1	Pathogenic	0.000000
97.	c.2429_2503delins23	p.Arg810Profs*10	frameshift	1	Pathogenic	0.000000
98.	c.982delG		frameshift	1	Pathogenic	0.000000
99.	c.1458G>A	p.W486X	nonsense	1	Pathogenic	0.000000
100.	c.1120C>T	p.Q374X	nonsense	1	Pathogenic	0.000000
101.	c.2065C>T	p.Q689X	nonsense	1	Pathogenic	0.000000
102.	c.1352_1353del	p.Glu451Alafs*23	frameshift	1	Pathogenic	0.000000
103.	c.255del	p.Ser86Profs*10	frameshift	1	Pathogenic	0.000000
104.	c.553_562del	p.Lys185Trpfs*12	frameshift	1	Pathogenic	0.000000
105.	c.1828G>C	p.D610H	missense	1	VUS	0.000058
106.	c.3316del	p.Asp1106Thrfs*83	frameshift	1	Pathogenic	0.000000
107.	c.1021_1028del	p.Gly341*	frameshift	1	Pathogenic	0.000000
108.	c.1898-1G>A		essential splice site	1	Pathogenic	0.000000
109.	c.121dup	p.Arg41Profs*8	frameshift	1	Pathogenic	0.000000
110.	c.1789C>T	p.R597W	missense	1	VUS	0.000038
111.	c.3253G>T	p.E1085X	nonsense	1	Pathogenic	0.000000
112.	c.3676C>T	p.R1226C	missense	1	VUS	0.000058
113.	c.1591G>A	p.G531R	missense	1	Likely Pathogenic	0.000017
114.	c.2807dup	p.Ala938Glyfs*113	frameshift	1	Pathogenic	0.000000
115.	c.1291G>A	p.D431N	missense	1	VUS	0.000028
116.	c.2249C>T	p.T750M	missense	1	Likely Pathogenic	0.000024
117.	c.3206C>A	p.P1069H	missense	1	Likely Pathogenic	0.000000
118.	c.2371C>T	p.Q791X	nonsense	1	Pathogenic	0.000000
119.	c.821+1G>A		essential splice site	1	Pathogenic	0.000043
120.	c.1021G>A	p.G341S	missense	1	VUS	0.000025
121.	c.2718_2719dup	p.Glu907Glyfs*18	frameshift	1	Pathogenic	0.000000
122.	c.711C>A	p.Y237X	nonsense	1	Pathogenic	0.000000
123.	c.3728C>G	p.P1243R	missense	1	VUS	0.000000
124.	c.631G>A	p.D211N	missense	1	VUS	0.000009
125.	c.1201C>T	p.Q401X	nonsense	1	Pathogenic	0.000000
126.	c.2161_2168del	p.Thr721Profs*23	frameshift	1	Pathogenic	0.000000
127.	c.49C>T	p.R17W	missense	1	VUS	0.000023
128.	c.1376_1377del	p.Pro459Leufs*15	frameshift	1	Pathogenic	0.000000
129.	c.2381C>A	p.P794Q	missense	1	VUS	0.000000
130.	c.373G>T	p.A125S	missense	1	VUS	0.000000
131.	c.1569dup	p.His524Alafs*7	frameshift	1	Pathogenic	0.000000
132.	c.3334_3351del	p.Trp1112_Glu1117del	inframe	1	Likely Pathogenic	0.000000
133.	c.1080G>C	p.K360N	missense	1	VUS	0.000000
134.	c.2198G>A	p.R733H	missense	1	VUS	0.000034
135.	c.351_352del	p.Gly118Argfs*8	frameshift	1	Pathogenic	0.000000
136.	c.1224-1G>T		essential splice site	1	Pathogenic	0.000000
137.	c.655-2del		essential splice site	1	Pathogenic	0.000000
138.	c.391dup	p.Ala131Glyfs*22	frameshift	1	Pathogenic	0.000000
139.	c.1999_2000delinsG	p.Leu667AspfsX15	frameshift	1	Pathogenic	0.000000
140.	c.177dup	p.Glu60Argfs*53	frameshift	1	Pathogenic	0.000000
141.	c.2304_2308+2delCATCGGT		essential splice site	1	Pathogenic	0.000000
142.	c.2504G>T	p.R835L	missense	1	Likely Pathogenic	0.000074
143.	c.3617delG		frameshift	1	Pathogenic	0.000000
144.	c.3452C>T	p.A1151V	missense	1	VUS	0.000078
145.	c.1624+1G>A		essential splice site	1	Pathogenic	0.000000
146.	c.1037G>A	p.R346H	missense	1	VUS	0.000000
147.	c.2738-2A>G		essential splice site	1	Pathogenic	0.000000
148.	c.1213A>G	p.M405V	missense	1	VUS	0.000000
149.	c.2968C>G	p.P990A	missense	1	Likely Pathogenic	0.000000
150.	c.1377delC		frameshift	1	Pathogenic	0.000000
151.	c.2584C>T	p.Q862X	nonsense	1	Pathogenic	0.000000
152.	c.799C>G	p.L267V	missense	1	VUS	0.000080
153.	c.1405C>T	p.Q469X	nonsense	1	Pathogenic	0.000000
154.	c.2502del	p.Arg835Alafs*2	frameshift	1	Pathogenic	0.000000
155.	c.459delC		frameshift	1	Pathogenic	0.000000
156.	c.1756C>G	p.P586A	missense	1	Likely Pathogenic	0.000000
157.	c.2603-2_2603-1delinsGA		essential splice site	1	Pathogenic	0.000000
158.	c.1090+1G>A		essential splice site	1	Pathogenic	0.000000
159.	c.146_148delTCA	p.Ile49del	inframe	1	VUS	0.000039
160.	c.3792_3793del	p.Cys1264*	frameshift	1	Likely Pathogenic	0.000000
161.	c.1266_1267insTGAT	p.Ile423*	frameshift	1	Pathogenic	0.000000
162.	c.187C>T	p.R63W	missense	1	VUS	0.000077
163.	c.731del	p.Lys244Argfs*56	frameshift	1	Pathogenic	0.000000
164.	c.1457G>A	p.W486X	nonsense	1	Pathogenic	0.000000
165.	c.3364A>T	p.T1122S	missense	1	Likely Pathogenic	0.000000
166.	c.1097A>C	p.Q366P	missense	1	VUS	0.000000
167.	c.821+2T>G		essential splice site	1	Pathogenic	0.000000
168.	c.2030C>T	p.P677L	missense	1	VUS	0.000000
169.	c.241G>T	p.V81F	missense	1	VUS	0.000000
170.	c.3297dup	p.Tyr1100Valfs*49	frameshift	1	Pathogenic	0.000000
171.	c.1A>T	p.Met1?	missense	1	Likely Pathogenic	0.000000
172.	c.2534_2538delGCGTC		frameshift	1	Pathogenic	0.000000
173.	c.2909G>A	p.R970Q	missense	1	Likely Pathogenic	0.000032
174.	c.2449C>T	p.R817W	missense	1	VUS	0.000000
175.	c.3490+1G>A		essential splice site	1	Pathogenic	0.000000
176.	c.3373G>A	p.V1125M	missense	1	VUS	0.000022
177.	c.1456T>G	p.W486G	missense	1	VUS	0.000000
178.	c.3064C>T	p.R1022C	missense	1	VUS	0.000008
179.	c.3656T>C	p.L1219P	missense	1	VUS	0.000000
180.	c.2789del	p.Leu930Argfs*2	frameshift	1	Pathogenic	0.000000
181.	c.2708G>A	p.G903D	missense	1	Likely Pathogenic	0.000000
182.	c.1112C>T	p.P371L	missense	1	VUS	0.000028
183.	c.2834G>A	p.R945Q	missense	1	VUS	0.000000
184.	c.1303C>T	p.Q435X	nonsense	1	Pathogenic	0.000000
185.	c.2512dup	p.Glu838Glyfs*46	frameshift	1	Pathogenic	0.000000
186.	c.994G>A	p.E332K	missense	1	VUS	0.000009
187.	c.532G>A	p.V178M	missense	1	VUS	0.000020
188.	c.188G>A	p.R63Q	missense	1	VUS	0.000039
189.	c.1523_1525delinsT	p.Gln508Leufs*22	frameshift	1	Pathogenic	0.000000
190.	c.3614G>C	p.R1205P	missense	1	Likely Pathogenic	0.000000
191.	c.1174G>T	p.A392S	missense	1	VUS	0.000000
192.	c.2054_2067+11del	p.Lys685Argfs*3	frameshift	1	Pathogenic	0.000000
193.	c.*26+2T>C		essential splice site	1	Likely Pathogenic	0.000000
194.	c.1359del	p.Val454Cysfs*12	frameshift	1	Pathogenic	0.000000
195.	c.611_618delinsT	p.Gly204Valfs*94	frameshift	1	Pathogenic	0.000000
196.	c.1841A>G	p.Y614C	missense	1	VUS	0.000000
197.	c.3330+1G>C		essential splice site	1	Pathogenic	0.000000
198.	c.100_110dup	p.Val38Serfs*5	frameshift	1	Pathogenic	0.000000
199.	c.1038_1042dupCGGCA		frameshift	1	Pathogenic	0.000008
200.	c.2197C>T	p.R733C	missense	1	Likely Pathogenic	0.000085
201.	c.3739G>A	p.D1247N	missense	1	VUS	0.000000
202.	c.256_258del	p.Ser86del	inframe	1	VUS	0.000000
203.	c.1223+2T>C		essential splice site	1	Pathogenic	0.000000
204.	c.2953A>T	p.K985X	nonsense	1	Pathogenic	0.000000
205.	c.1790G>A	p.R597Q	missense	1	VUS	0.000000
206.	c.2873C>T	p.T958I	missense	1	VUS	0.000065
207.	c.3257G>A	p.W1086X	nonsense	1	Pathogenic	0.000021
208.	c.3811C>T	p.R1271X	nonsense	1	VUS	0.000025
209.	c.2503C>T	p.R835C	missense	1	VUS	0.000024
210.	c.3614G>A	p.R1205Q	missense	1	VUS	0.000016
211.	c.2265C>A	p.N755K	missense	1	Pathogenic	0.000000
212.	c.3256T>C	p.W1086R	missense	1	VUS	0.000000
213.	c.1471G>A	p.V491M	missense	1	VUS	0.000058
214.	c.1021G>C	p.G341R	missense	1	VUS	0.000000
215.	c.3572C>T	p.S1191L	missense	1	VUS	0.000016
216.	c.2149_2737del	p.Leu717Alafs*11	frameshift	1	Pathogenic	0.000000
217.	c.1153G>A	p.V385M	missense	1	VUS	0.000010
218.	c.743_746delACTG		frameshift	1	Pathogenic	0.000000
219.	c.2953A>G	p.K985E	missense	1	Pathogenic	0.000000
220.	c.1351+1G>A		essential splice site	1	Pathogenic	0.000000
221.	c.2188del	p.Thr730Profs*24	frameshift	1	Pathogenic	0.000000
222.	c.148A>G	p.S50G	missense	1	VUS	0.000038
223.	c.772+1G>A		essential splice site	1	Pathogenic	0.000000
224.	c.1404del	p.Gln469Serfs*19	frameshift	1	Pathogenic	0.000000
225.	c.932C>A	p.S311X	nonsense	1	Pathogenic	0.000000
226.	c.1731G>C	p.W577C	missense	1	VUS	0.000000
227.	c.3357C>A	p.Y1119X	nonsense	1	Pathogenic	0.000000
228.	c.1090+2T>C		essential splice site	1	Pathogenic	0.000000
229.	c.365C>A	p.A122D	missense	1	VUS	0.000000
230.	c.1231A>G	p.I411V	missense	1	VUS	0.000000
231.	c.701C>A	p.T234N	missense	1	Likely Pathogenic	0.000000
232.	c.1455A>T	p.K485N	missense	1	VUS	0.000000
233.	c.211_212delinsTA	p.Val71*	frameshift	1	Pathogenic	0.000000
234.	c.2995-1G>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.