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.1483C>G	p.R495G	missense	10	Likely Pathogenic	0.000000
11.	c.1928-2A>G		essential splice site	10	Pathogenic	0.000000
12.	c.3613C>T	p.R1205W	missense	10	Likely Pathogenic	0.000016
13.	c.3771C>A	p.N1257K	missense	9	Likely Pathogenic	0.000000
14.	c.927-2A>G		essential splice site	8	Pathogenic	0.000000
15.	c.2864_2865delCT		frameshift	8	Pathogenic	0.000000
16.	c.2604_2605delinsA	p.S871fs	frameshift	8	Pathogenic	0.000000
17.	c.2490_2491insT	p.His831SerfsTer2	frameshift	7	Pathogenic	0.000024
18.	c.3190+2T>G		essential splice site	7	Pathogenic	0.000016
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.2556_2557delinsTCT	p.Gly853fs	frameshift	4	Pathogenic	0.000000
26.	c.1484G>A	p.R495Q	missense	4	Likely Pathogenic	0.000008
27.	c.821+2T>C		essential splice site	4	Pathogenic	0.000000
28.	c.442G>A	p.G148R	missense	4	Likely Pathogenic	0.000042
29.	c.3798C>G	p.C1266W	missense	4	VUS	0.000000
30.	c.3163A>T	p.K1055X	nonsense	4	Pathogenic	0.000000
31.	c.484C>T	p.Q162X	nonsense	4	Pathogenic	0.000000
32.	c.3697C>T	p.Q1233X	nonsense	4	Likely Pathogenic	0.000008
33.	c.3763G>A	p.A1255T	missense	3	VUS	0.000075
34.	c.3408C>A	p.Y1136X	nonsense	3	Pathogenic	0.000000
35.	c.3600_3609delCTGCTGTGCT		frameshift	3	Pathogenic	0.000000
36.	c.2545del	p.Val849Serfs*30	frameshift	3	Pathogenic	0.000000
37.	c.3277G>T	p.G1093C	missense	3	VUS	0.000020
38.	c.710A>C	p.Y237S	missense	3	Likely Pathogenic	0.000000
39.	c.3181C>T	p.Q1061X	nonsense	3	Pathogenic	0.000016
40.	c.1720C>T	p.R574W	missense	3	VUS	0.000054
41.	c.3286G>T	p.E1096X	nonsense	3	Pathogenic	0.000000
42.	c.2210C>T	p.T737M	missense	3	VUS	0.000050
43.	c.3129C>A	p.Y1043X	nonsense	3	Pathogenic	0.000000
44.	c.2309-1G>A		essential splice site	3	Pathogenic	0.000000
45.	c.2905+1G>A		essential splice site	3	Pathogenic	0.000000
46.	c.1123G>A	p.V375M	missense	3	VUS	0.000009
47.	c.2573G>A	p.S858N	missense	2	Likely Pathogenic	0.000000
48.	c.443dup	p.Ala149Serfs*4	frameshift	2	Pathogenic	0.000000
49.	c.818G>A	p.R273H	missense	2	VUS	0.000042
50.	c.3470C>T	p.P1157L	missense	2	VUS	0.000093
51.	c.2905C>T	p.Q969X	nonsense	2	Pathogenic	0.000000
52.	c.1828G>A	p.D610N	missense	2	VUS	0.000000
53.	c.2432A>G	p.K811R	missense	2	VUS	0.000000
54.	c.747C>A	p.C249X	nonsense	2	Pathogenic	0.000000
55.	c.25+1G>A		essential splice site	2	Pathogenic	0.000000
56.	c.1505G>A	p.R502Q	missense	2	Pathogenic	0.000000
57.	c.3005G>A	p.R1002Q	missense	2	VUS	0.000046
58.	c.3627+1G>T		essential splice site	2	Pathogenic	0.000000
59.	c.3752A>G	p.Y1251C	missense	2	VUS	0.000000
60.	c.2905+2dup		essential splice site	2	Likely Pathogenic	0.000000
61.	c.2524dup	p.Tyr842Leufs*42	frameshift	2	Pathogenic	0.000000
62.	c.2300A>G	p.K767R	missense	2	VUS	0.000016
63.	c.1483C>T	p.R495W	missense	2	Likely Pathogenic	0.000000
64.	c.557C>T	p.P186L	missense	2	VUS	0.000047
65.	c.3271del	p.Asp1091Metfs*98	frameshift	2	Pathogenic	0.000000
66.	c.177_187del	p.Glu60AlafsX49	frameshift	2	Pathogenic	0.000000
67.	c.3455_3466del	p.Ala1152_Lys1155del	inframe	2	Likely Pathogenic	0.000000
68.	c.2308+1G>A		essential splice site	2	Pathogenic	0.000000
69.	c.2219G>C	p.G740A	missense	2	VUS	0.000000
70.	c.3751T>C	p.Y1251H	missense	2	VUS	0.000000
71.	c.3582_3593delGGGCTACACTGC		inframe	2	Likely Pathogenic	0.000000
72.	c.1886T>C	p.L629P	missense	2	VUS	0.000000
73.	c.2526C>G	p.Y842X	nonsense	2	Pathogenic	0.000000
74.	c.126G>A	p.W42X	nonsense	2	Pathogenic	0.000000
75.	c.833delG	p.Gly278GlufsX22	frameshift	2	Pathogenic	0.000000
76.	c.146_148delTCA	p.Ile49del	inframe	1	VUS	0.000039
77.	c.799C>G	p.L267V	missense	1	VUS	0.000080
78.	c.459delC		frameshift	1	Pathogenic	0.000000
79.	c.3253G>T	p.E1085X	nonsense	1	Pathogenic	0.000000
80.	c.3364A>T	p.T1122S	missense	1	Likely Pathogenic	0.000000
81.	c.3656T>C	p.L1219P	missense	1	VUS	0.000000
82.	c.3792_3793del	p.Cys1264*	frameshift	1	Likely Pathogenic	0.000000
83.	c.3256T>C	p.W1086R	missense	1	VUS	0.000000
84.	c.187C>T	p.R63W	missense	1	VUS	0.000077
85.	c.2953A>G	p.K985E	missense	1	Pathogenic	0.000000
86.	c.3297dup	p.Tyr1100Valfs*49	frameshift	1	Pathogenic	0.000000
87.	c.2149_2737del	p.Leu717Alafs*11	frameshift	1	Pathogenic	0.000000
88.	c.2188del	p.Thr730Profs*24	frameshift	1	Pathogenic	0.000000
89.	c.1404del	p.Gln469Serfs*19	frameshift	1	Pathogenic	0.000000
90.	c.2198G>A	p.R733H	missense	1	VUS	0.000034
91.	c.1731G>C	p.W577C	missense	1	VUS	0.000000
92.	c.1624+1G>A		essential splice site	1	Pathogenic	0.000000
93.	c.1090+2T>C		essential splice site	1	Pathogenic	0.000000
94.	c.2249C>T	p.T750M	missense	1	Likely Pathogenic	0.000024
95.	c.365C>A	p.A122D	missense	1	VUS	0.000000
96.	c.1231A>G	p.I411V	missense	1	VUS	0.000000
97.	c.701C>A	p.T234N	missense	1	Likely Pathogenic	0.000000
98.	c.1999_2000delinsG	p.Leu667AspfsX15	frameshift	1	Pathogenic	0.000000
99.	c.1455A>T	p.K485N	missense	1	VUS	0.000000
100.	c.1037G>A	p.R346H	missense	1	VUS	0.000000
101.	c.1213A>G	p.M405V	missense	1	VUS	0.000000
102.	c.211_212delinsTA	p.Val71*	frameshift	1	Pathogenic	0.000000
103.	c.1377delC		frameshift	1	Pathogenic	0.000000
104.	c.532G>A	p.V178M	missense	1	VUS	0.000020
105.	c.3811C>T	p.R1271X	nonsense	1	VUS	0.000025
106.	c.1090+1G>A		essential splice site	1	Pathogenic	0.000000
107.	c.*26+2T>C		essential splice site	1	Likely Pathogenic	0.000000
108.	c.3614G>A	p.R1205Q	missense	1	VUS	0.000016
109.	c.188G>A	p.R63Q	missense	1	VUS	0.000039
110.	c.3614G>C	p.R1205P	missense	1	Likely Pathogenic	0.000000
111.	c.2748G>A	p.W916X	nonsense	1	Pathogenic	0.000000
112.	c.3316G>A	p.D1106N	missense	1	VUS	0.000061
113.	c.3739G>A	p.D1247N	missense	1	VUS	0.000000
114.	c.3043dup	p.Ala1015Glyfs*36	frameshift	1	Pathogenic	0.000000
115.	c.3572C>T	p.S1191L	missense	1	VUS	0.000016
116.	c.2603-1G>C		essential splice site	1	Pathogenic	0.000000
117.	c.3330+1G>C		essential splice site	1	Pathogenic	0.000000
118.	c.1797del	p.His599Glnfs*3	frameshift	1	Pathogenic	0.000000
119.	c.2690_2696del	p.Gly897Glufs*25	frameshift	1	Pathogenic	0.000000
120.	c.2304_2308+2delCATCGGT		essential splice site	1	Pathogenic	0.000000
121.	c.2247C>A	p.Y749X	nonsense	1	Pathogenic	0.000000
122.	c.2504G>T	p.R835L	missense	1	Likely Pathogenic	0.000074
123.	c.2429_2503delins23	p.Arg810Profs*10	frameshift	1	Pathogenic	0.000000
124.	c.1352_1353del	p.Glu451Alafs*23	frameshift	1	Pathogenic	0.000000
125.	c.2030C>T	p.P677L	missense	1	VUS	0.000000
126.	c.1458G>A	p.W486X	nonsense	1	Pathogenic	0.000000
127.	c.1120C>T	p.Q374X	nonsense	1	Pathogenic	0.000000
128.	c.2065C>T	p.Q689X	nonsense	1	Pathogenic	0.000000
129.	c.255del	p.Ser86Profs*10	frameshift	1	Pathogenic	0.000000
130.	c.1456T>G	p.W486G	missense	1	VUS	0.000000
131.	c.553_562del	p.Lys185Trpfs*12	frameshift	1	Pathogenic	0.000000
132.	c.1021_1028del	p.Gly341*	frameshift	1	Pathogenic	0.000000
133.	c.743_746delACTG		frameshift	1	Pathogenic	0.000000
134.	c.1112C>T	p.P371L	missense	1	VUS	0.000028
135.	c.121dup	p.Arg41Profs*8	frameshift	1	Pathogenic	0.000000
136.	c.1303C>T	p.Q435X	nonsense	1	Pathogenic	0.000000
137.	c.994G>A	p.E332K	missense	1	VUS	0.000009
138.	c.3713T>C	p.L1238P	missense	1	Likely Pathogenic	0.000000
139.	c.148A>G	p.S50G	missense	1	VUS	0.000038
140.	c.772+1G>A		essential splice site	1	Pathogenic	0.000000
141.	c.3624delC		frameshift	1	Pathogenic	0.000000
142.	c.3206C>A	p.P1069H	missense	1	Likely Pathogenic	0.000000
143.	c.3605delG		frameshift	1	Pathogenic	0.000000
144.	c.3357C>A	p.Y1119X	nonsense	1	Pathogenic	0.000000
145.	c.2807dup	p.Ala938Glyfs*113	frameshift	1	Pathogenic	0.000000
146.	c.2371C>T	p.Q791X	nonsense	1	Pathogenic	0.000000
147.	c.2909G>A	p.R970Q	missense	1	Likely Pathogenic	0.000032
148.	c.2534_2538delGCGTC		frameshift	1	Pathogenic	0.000000
149.	c.3064C>T	p.R1022C	missense	1	VUS	0.000008
150.	c.2718_2719dup	p.Glu907Glyfs*18	frameshift	1	Pathogenic	0.000000
151.	c.2558delG		frameshift	1	Pathogenic	0.000000
152.	c.1201C>T	p.Q401X	nonsense	1	Pathogenic	0.000000
153.	c.2161_2168del	p.Thr721Profs*23	frameshift	1	Pathogenic	0.000000
154.	c.1841A>G	p.Y614C	missense	1	VUS	0.000000
155.	c.1376_1377del	p.Pro459Leufs*15	frameshift	1	Pathogenic	0.000000
156.	c.2449C>T	p.R817W	missense	1	VUS	0.000000
157.	c.2381C>A	p.P794Q	missense	1	VUS	0.000000
158.	c.2197C>T	p.R733C	missense	1	Likely Pathogenic	0.000085
159.	c.1569dup	p.His524Alafs*7	frameshift	1	Pathogenic	0.000000
160.	c.1471G>A	p.V491M	missense	1	VUS	0.000058
161.	c.655-2del		essential splice site	1	Pathogenic	0.000000
162.	c.1080G>C	p.K360N	missense	1	VUS	0.000000
163.	c.351_352del	p.Gly118Argfs*8	frameshift	1	Pathogenic	0.000000
164.	c.1790G>A	p.R597Q	missense	1	VUS	0.000000
165.	c.1224-1G>T		essential splice site	1	Pathogenic	0.000000
166.	c.844C>T	p.R282W	missense	1	Likely Pathogenic	0.000000
167.	c.1351+1G>A		essential splice site	1	Pathogenic	0.000000
168.	c.391dup	p.Ala131Glyfs*22	frameshift	1	Pathogenic	0.000000
169.	c.1021G>C	p.G341R	missense	1	VUS	0.000000
170.	c.1153G>A	p.V385M	missense	1	VUS	0.000010
171.	c.177dup	p.Glu60Argfs*53	frameshift	1	Pathogenic	0.000000
172.	c.811_817delTTCCGCC		frameshift	1	Pathogenic	0.000000
173.	c.506-1G>A		essential splice site	1	Pathogenic	0.000000
174.	c.932C>A	p.S311X	nonsense	1	Pathogenic	0.000000
175.	c.3676C>T	p.R1226C	missense	1	VUS	0.000058
176.	c.3452C>T	p.A1151V	missense	1	VUS	0.000078
177.	c.3257G>A	p.W1086X	nonsense	1	Pathogenic	0.000021
178.	c.2584C>T	p.Q862X	nonsense	1	Pathogenic	0.000000
179.	c.3316del	p.Asp1106Thrfs*83	frameshift	1	Pathogenic	0.000000
180.	c.2738-2A>G		essential splice site	1	Pathogenic	0.000000
181.	c.2953A>T	p.K985X	nonsense	1	Pathogenic	0.000000
182.	c.2968C>G	p.P990A	missense	1	Likely Pathogenic	0.000000
183.	c.1405C>T	p.Q469X	nonsense	1	Pathogenic	0.000000
184.	c.2503C>T	p.R835C	missense	1	VUS	0.000024
185.	c.2502del	p.Arg835Alafs*2	frameshift	1	Pathogenic	0.000000
186.	c.1756C>G	p.P586A	missense	1	Likely Pathogenic	0.000000
187.	c.2603-2_2603-1delinsGA		essential splice site	1	Pathogenic	0.000000
188.	c.2873C>T	p.T958I	missense	1	VUS	0.000065
189.	c.1266_1267insTGAT	p.Ile423*	frameshift	1	Pathogenic	0.000000
190.	c.731del	p.Lys244Argfs*56	frameshift	1	Pathogenic	0.000000
191.	c.1457G>A	p.W486X	nonsense	1	Pathogenic	0.000000
192.	c.1685C>T	p.A562V	missense	1	VUS	0.000008
193.	c.1097A>C	p.Q366P	missense	1	VUS	0.000000
194.	c.2265C>A	p.N755K	missense	1	Pathogenic	0.000000
195.	c.1A>T	p.Met1?	missense	1	Likely Pathogenic	0.000000
196.	c.821+2T>G		essential splice site	1	Pathogenic	0.000000
197.	c.1273C>T	p.Q425X	nonsense	1	Pathogenic	0.000000
198.	c.241G>T	p.V81F	missense	1	VUS	0.000000
199.	c.1433C>T	p.S478L	missense	1	Likely Pathogenic	0.000017
200.	c.1072G>A	p.D358N	missense	1	VUS	0.000008
201.	c.982delG		frameshift	1	Pathogenic	0.000000
202.	c.711C>A	p.Y237X	nonsense	1	Pathogenic	0.000000
203.	c.1090+1G>T		essential splice site	1	Pathogenic	0.000000
204.	c.821+1G>A		essential splice site	1	Pathogenic	0.000043
205.	c.3617delG		frameshift	1	Pathogenic	0.000000
206.	c.373G>T	p.A125S	missense	1	VUS	0.000000
207.	c.3728C>G	p.P1243R	missense	1	VUS	0.000000
208.	c.631G>A	p.D211N	missense	1	VUS	0.000009
209.	c.3490+1G>A		essential splice site	1	Pathogenic	0.000000
210.	c.49C>T	p.R17W	missense	1	VUS	0.000023
211.	c.3373G>A	p.V1125M	missense	1	VUS	0.000022
212.	c.2995-1G>A		essential splice site	1	Pathogenic	0.000000
213.	c.3334_3351del	p.Trp1112_Glu1117del	inframe	1	Likely Pathogenic	0.000000
214.	c.2789del	p.Leu930Argfs*2	frameshift	1	Pathogenic	0.000000
215.	c.2708G>A	p.G903D	missense	1	Likely Pathogenic	0.000000
216.	c.2834G>A	p.R945Q	missense	1	VUS	0.000000
217.	c.2512dup	p.Glu838Glyfs*46	frameshift	1	Pathogenic	0.000000
218.	c.3019T>C	p.W1007R	missense	1	VUS	0.000000
219.	c.1523_1525delinsT	p.Gln508Leufs*22	frameshift	1	Pathogenic	0.000000
220.	c.1174G>T	p.A392S	missense	1	VUS	0.000000
221.	c.2269G>A	p.V757M	missense	1	VUS	0.000066
222.	c.2054_2067+11del	p.Lys685Argfs*3	frameshift	1	Pathogenic	0.000000
223.	c.1828G>C	p.D610H	missense	1	VUS	0.000058
224.	c.1359del	p.Val454Cysfs*12	frameshift	1	Pathogenic	0.000000
225.	c.1223+2T>C		essential splice site	1	Pathogenic	0.000000
226.	c.611_618delinsT	p.Gly204Valfs*94	frameshift	1	Pathogenic	0.000000
227.	c.1898-1G>A		essential splice site	1	Pathogenic	0.000000
228.	c.100_110dup	p.Val38Serfs*5	frameshift	1	Pathogenic	0.000000
229.	c.1591G>A	p.G531R	missense	1	Likely Pathogenic	0.000017
230.	c.1038_1042dupCGGCA		frameshift	1	Pathogenic	0.000008
231.	c.1291G>A	p.D431N	missense	1	VUS	0.000028
232.	c.256_258del	p.Ser86del	inframe	1	VUS	0.000000
233.	c.1789C>T	p.R597W	missense	1	VUS	0.000038
234.	c.1021G>A	p.G341S	missense	1	VUS	0.000025

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.