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

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.