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