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.927-2A>G		essential splice site	8	Pathogenic	0.000000
15.	c.2604_2605delinsA	p.S871fs	frameshift	8	Pathogenic	0.000000
16.	c.2864_2865delCT		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.2267delC		frameshift	5	Pathogenic	0.000000
21.	c.3065G>C	p.R1022P	missense	5	Likely Pathogenic	0.000025
22.	c.2308G>A	p.D770N	missense	5	Likely Pathogenic	0.000008
23.	c.2459G>A	p.R820Q	missense	5	VUS	0.000016
24.	c.2610delC		frameshift	5	Pathogenic	0.000000
25.	c.3697C>T	p.Q1233X	nonsense	4	Likely Pathogenic	0.000008
26.	c.3163A>T	p.K1055X	nonsense	4	Pathogenic	0.000000
27.	c.484C>T	p.Q162X	nonsense	4	Pathogenic	0.000000
28.	c.821+2T>C		essential splice site	4	Pathogenic	0.000000
29.	c.442G>A	p.G148R	missense	4	Likely Pathogenic	0.000042
30.	c.2556_2557delinsTCT	p.Gly853fs	frameshift	4	Pathogenic	0.000000
31.	c.3798C>G	p.C1266W	missense	4	VUS	0.000000
32.	c.1484G>A	p.R495Q	missense	4	Likely Pathogenic	0.000008
33.	c.1720C>T	p.R574W	missense	3	VUS	0.000054
34.	c.3129C>A	p.Y1043X	nonsense	3	Pathogenic	0.000000
35.	c.2309-1G>A		essential splice site	3	Pathogenic	0.000000
36.	c.3763G>A	p.A1255T	missense	3	VUS	0.000075
37.	c.2545del	p.Val849Serfs*30	frameshift	3	Pathogenic	0.000000
38.	c.3286G>T	p.E1096X	nonsense	3	Pathogenic	0.000000
39.	c.710A>C	p.Y237S	missense	3	Likely Pathogenic	0.000000
40.	c.2210C>T	p.T737M	missense	3	VUS	0.000050
41.	c.2905+1G>A		essential splice site	3	Pathogenic	0.000000
42.	c.1123G>A	p.V375M	missense	3	VUS	0.000009
43.	c.3600_3609delCTGCTGTGCT		frameshift	3	Pathogenic	0.000000
44.	c.3408C>A	p.Y1136X	nonsense	3	Pathogenic	0.000000
45.	c.3277G>T	p.G1093C	missense	3	VUS	0.000020
46.	c.3181C>T	p.Q1061X	nonsense	3	Pathogenic	0.000016
47.	c.1828G>A	p.D610N	missense	2	VUS	0.000000
48.	c.2432A>G	p.K811R	missense	2	VUS	0.000000
49.	c.747C>A	p.C249X	nonsense	2	Pathogenic	0.000000
50.	c.1505G>A	p.R502Q	missense	2	Pathogenic	0.000000
51.	c.25+1G>A		essential splice site	2	Pathogenic	0.000000
52.	c.3751T>C	p.Y1251H	missense	2	VUS	0.000000
53.	c.1886T>C	p.L629P	missense	2	VUS	0.000000
54.	c.3005G>A	p.R1002Q	missense	2	VUS	0.000046
55.	c.833delG	p.Gly278GlufsX22	frameshift	2	Pathogenic	0.000000
56.	c.2300A>G	p.K767R	missense	2	VUS	0.000016
57.	c.1483C>T	p.R495W	missense	2	Likely Pathogenic	0.000000
58.	c.2308+1G>A		essential splice site	2	Pathogenic	0.000000
59.	c.818G>A	p.R273H	missense	2	VUS	0.000042
60.	c.3582_3593delGGGCTACACTGC		inframe	2	Likely Pathogenic	0.000000
61.	c.2526C>G	p.Y842X	nonsense	2	Pathogenic	0.000000
62.	c.3752A>G	p.Y1251C	missense	2	VUS	0.000000
63.	c.3627+1G>T		essential splice site	2	Pathogenic	0.000000
64.	c.2524dup	p.Tyr842Leufs*42	frameshift	2	Pathogenic	0.000000
65.	c.126G>A	p.W42X	nonsense	2	Pathogenic	0.000000
66.	c.2905+2dup		essential splice site	2	Likely Pathogenic	0.000000
67.	c.2573G>A	p.S858N	missense	2	Likely Pathogenic	0.000000
68.	c.3271del	p.Asp1091Metfs*98	frameshift	2	Pathogenic	0.000000
69.	c.177_187del	p.Glu60AlafsX49	frameshift	2	Pathogenic	0.000000
70.	c.3455_3466del	p.Ala1152_Lys1155del	inframe	2	Likely Pathogenic	0.000000
71.	c.557C>T	p.P186L	missense	2	VUS	0.000047
72.	c.443dup	p.Ala149Serfs*4	frameshift	2	Pathogenic	0.000000
73.	c.2219G>C	p.G740A	missense	2	VUS	0.000000
74.	c.3470C>T	p.P1157L	missense	2	VUS	0.000093
75.	c.2905C>T	p.Q969X	nonsense	2	Pathogenic	0.000000
76.	c.3728C>G	p.P1243R	missense	1	VUS	0.000000
77.	c.631G>A	p.D211N	missense	1	VUS	0.000009
78.	c.1120C>T	p.Q374X	nonsense	1	Pathogenic	0.000000
79.	c.49C>T	p.R17W	missense	1	VUS	0.000023
80.	c.373G>T	p.A125S	missense	1	VUS	0.000000
81.	c.2030C>T	p.P677L	missense	1	VUS	0.000000
82.	c.553_562del	p.Lys185Trpfs*12	frameshift	1	Pathogenic	0.000000
83.	c.3334_3351del	p.Trp1112_Glu1117del	inframe	1	Likely Pathogenic	0.000000
84.	c.1021_1028del	p.Gly341*	frameshift	1	Pathogenic	0.000000
85.	c.2789del	p.Leu930Argfs*2	frameshift	1	Pathogenic	0.000000
86.	c.255del	p.Ser86Profs*10	frameshift	1	Pathogenic	0.000000
87.	c.1456T>G	p.W486G	missense	1	VUS	0.000000
88.	c.1303C>T	p.Q435X	nonsense	1	Pathogenic	0.000000
89.	c.2512dup	p.Glu838Glyfs*46	frameshift	1	Pathogenic	0.000000
90.	c.2708G>A	p.G903D	missense	1	Likely Pathogenic	0.000000
91.	c.1112C>T	p.P371L	missense	1	VUS	0.000028
92.	c.121dup	p.Arg41Profs*8	frameshift	1	Pathogenic	0.000000
93.	c.2834G>A	p.R945Q	missense	1	VUS	0.000000
94.	c.2054_2067+11del	p.Lys685Argfs*3	frameshift	1	Pathogenic	0.000000
95.	c.1359del	p.Val454Cysfs*12	frameshift	1	Pathogenic	0.000000
96.	c.3624delC		frameshift	1	Pathogenic	0.000000
97.	c.1523_1525delinsT	p.Gln508Leufs*22	frameshift	1	Pathogenic	0.000000
98.	c.1223+2T>C		essential splice site	1	Pathogenic	0.000000
99.	c.3605delG		frameshift	1	Pathogenic	0.000000
100.	c.3064C>T	p.R1022C	missense	1	VUS	0.000008
101.	c.1021G>A	p.G341S	missense	1	VUS	0.000025
102.	c.2909G>A	p.R970Q	missense	1	Likely Pathogenic	0.000032
103.	c.2534_2538delGCGTC		frameshift	1	Pathogenic	0.000000
104.	c.1841A>G	p.Y614C	missense	1	VUS	0.000000
105.	c.2449C>T	p.R817W	missense	1	VUS	0.000000
106.	c.459delC		frameshift	1	Pathogenic	0.000000
107.	c.2197C>T	p.R733C	missense	1	Likely Pathogenic	0.000085
108.	c.2558delG		frameshift	1	Pathogenic	0.000000
109.	c.1201C>T	p.Q401X	nonsense	1	Pathogenic	0.000000
110.	c.146_148delTCA	p.Ile49del	inframe	1	VUS	0.000039
111.	c.799C>G	p.L267V	missense	1	VUS	0.000080
112.	c.3792_3793del	p.Cys1264*	frameshift	1	Likely Pathogenic	0.000000
113.	c.1790G>A	p.R597Q	missense	1	VUS	0.000000
114.	c.351_352del	p.Gly118Argfs*8	frameshift	1	Pathogenic	0.000000
115.	c.3256T>C	p.W1086R	missense	1	VUS	0.000000
116.	c.187C>T	p.R63W	missense	1	VUS	0.000077
117.	c.1471G>A	p.V491M	missense	1	VUS	0.000058
118.	c.655-2del		essential splice site	1	Pathogenic	0.000000
119.	c.3656T>C	p.L1219P	missense	1	VUS	0.000000
120.	c.3364A>T	p.T1122S	missense	1	Likely Pathogenic	0.000000
121.	c.1080G>C	p.K360N	missense	1	VUS	0.000000
122.	c.2149_2737del	p.Leu717Alafs*11	frameshift	1	Pathogenic	0.000000
123.	c.1153G>A	p.V385M	missense	1	VUS	0.000010
124.	c.177dup	p.Glu60Argfs*53	frameshift	1	Pathogenic	0.000000
125.	c.2953A>G	p.K985E	missense	1	Pathogenic	0.000000
126.	c.1351+1G>A		essential splice site	1	Pathogenic	0.000000
127.	c.391dup	p.Ala131Glyfs*22	frameshift	1	Pathogenic	0.000000
128.	c.3297dup	p.Tyr1100Valfs*49	frameshift	1	Pathogenic	0.000000
129.	c.1731G>C	p.W577C	missense	1	VUS	0.000000
130.	c.2188del	p.Thr730Profs*24	frameshift	1	Pathogenic	0.000000
131.	c.1404del	p.Gln469Serfs*19	frameshift	1	Pathogenic	0.000000
132.	c.1231A>G	p.I411V	missense	1	VUS	0.000000
133.	c.3257G>A	p.W1086X	nonsense	1	Pathogenic	0.000021
134.	c.1455A>T	p.K485N	missense	1	VUS	0.000000
135.	c.3452C>T	p.A1151V	missense	1	VUS	0.000078
136.	c.2953A>T	p.K985X	nonsense	1	Pathogenic	0.000000
137.	c.1037G>A	p.R346H	missense	1	VUS	0.000000
138.	c.3811C>T	p.R1271X	nonsense	1	VUS	0.000025
139.	c.2873C>T	p.T958I	missense	1	VUS	0.000065
140.	c.2503C>T	p.R835C	missense	1	VUS	0.000024
141.	c.532G>A	p.V178M	missense	1	VUS	0.000020
142.	c.731del	p.Lys244Argfs*56	frameshift	1	Pathogenic	0.000000
143.	c.3614G>C	p.R1205P	missense	1	Likely Pathogenic	0.000000
144.	c.1685C>T	p.A562V	missense	1	VUS	0.000008
145.	c.2265C>A	p.N755K	missense	1	Pathogenic	0.000000
146.	c.1097A>C	p.Q366P	missense	1	VUS	0.000000
147.	c.*26+2T>C		essential splice site	1	Likely Pathogenic	0.000000
148.	c.188G>A	p.R63Q	missense	1	VUS	0.000039
149.	c.3043dup	p.Ala1015Glyfs*36	frameshift	1	Pathogenic	0.000000
150.	c.1433C>T	p.S478L	missense	1	Likely Pathogenic	0.000017
151.	c.2603-1G>C		essential splice site	1	Pathogenic	0.000000
152.	c.3330+1G>C		essential splice site	1	Pathogenic	0.000000
153.	c.1A>T	p.Met1?	missense	1	Likely Pathogenic	0.000000
154.	c.821+2T>G		essential splice site	1	Pathogenic	0.000000
155.	c.2748G>A	p.W916X	nonsense	1	Pathogenic	0.000000
156.	c.3739G>A	p.D1247N	missense	1	VUS	0.000000
157.	c.1273C>T	p.Q425X	nonsense	1	Pathogenic	0.000000
158.	c.241G>T	p.V81F	missense	1	VUS	0.000000
159.	c.2247C>A	p.Y749X	nonsense	1	Pathogenic	0.000000
160.	c.2429_2503delins23	p.Arg810Profs*10	frameshift	1	Pathogenic	0.000000
161.	c.1797del	p.His599Glnfs*3	frameshift	1	Pathogenic	0.000000
162.	c.2690_2696del	p.Gly897Glufs*25	frameshift	1	Pathogenic	0.000000
163.	c.1090+1G>T		essential splice site	1	Pathogenic	0.000000
164.	c.3490+1G>A		essential splice site	1	Pathogenic	0.000000
165.	c.2065C>T	p.Q689X	nonsense	1	Pathogenic	0.000000
166.	c.1352_1353del	p.Glu451Alafs*23	frameshift	1	Pathogenic	0.000000
167.	c.3617delG		frameshift	1	Pathogenic	0.000000
168.	c.1458G>A	p.W486X	nonsense	1	Pathogenic	0.000000
169.	c.3373G>A	p.V1125M	missense	1	VUS	0.000022
170.	c.2995-1G>A		essential splice site	1	Pathogenic	0.000000
171.	c.3019T>C	p.W1007R	missense	1	VUS	0.000000
172.	c.994G>A	p.E332K	missense	1	VUS	0.000009
173.	c.743_746delACTG		frameshift	1	Pathogenic	0.000000
174.	c.1174G>T	p.A392S	missense	1	VUS	0.000000
175.	c.148A>G	p.S50G	missense	1	VUS	0.000038
176.	c.772+1G>A		essential splice site	1	Pathogenic	0.000000
177.	c.1828G>C	p.D610H	missense	1	VUS	0.000058
178.	c.3713T>C	p.L1238P	missense	1	Likely Pathogenic	0.000000
179.	c.2269G>A	p.V757M	missense	1	VUS	0.000066
180.	c.1591G>A	p.G531R	missense	1	Likely Pathogenic	0.000017
181.	c.100_110dup	p.Val38Serfs*5	frameshift	1	Pathogenic	0.000000
182.	c.1038_1042dupCGGCA		frameshift	1	Pathogenic	0.000008
183.	c.2807dup	p.Ala938Glyfs*113	frameshift	1	Pathogenic	0.000000
184.	c.1291G>A	p.D431N	missense	1	VUS	0.000028
185.	c.1789C>T	p.R597W	missense	1	VUS	0.000038
186.	c.256_258del	p.Ser86del	inframe	1	VUS	0.000000
187.	c.3206C>A	p.P1069H	missense	1	Likely Pathogenic	0.000000
188.	c.1898-1G>A		essential splice site	1	Pathogenic	0.000000
189.	c.611_618delinsT	p.Gly204Valfs*94	frameshift	1	Pathogenic	0.000000
190.	c.3357C>A	p.Y1119X	nonsense	1	Pathogenic	0.000000
191.	c.2718_2719dup	p.Glu907Glyfs*18	frameshift	1	Pathogenic	0.000000
192.	c.2371C>T	p.Q791X	nonsense	1	Pathogenic	0.000000
193.	c.1376_1377del	p.Pro459Leufs*15	frameshift	1	Pathogenic	0.000000
194.	c.2381C>A	p.P794Q	missense	1	VUS	0.000000
195.	c.1569dup	p.His524Alafs*7	frameshift	1	Pathogenic	0.000000
196.	c.2161_2168del	p.Thr721Profs*23	frameshift	1	Pathogenic	0.000000
197.	c.1224-1G>T		essential splice site	1	Pathogenic	0.000000
198.	c.3253G>T	p.E1085X	nonsense	1	Pathogenic	0.000000
199.	c.844C>T	p.R282W	missense	1	Likely Pathogenic	0.000000
200.	c.1021G>C	p.G341R	missense	1	VUS	0.000000
201.	c.506-1G>A		essential splice site	1	Pathogenic	0.000000
202.	c.932C>A	p.S311X	nonsense	1	Pathogenic	0.000000
203.	c.2198G>A	p.R733H	missense	1	VUS	0.000034
204.	c.811_817delTTCCGCC		frameshift	1	Pathogenic	0.000000
205.	c.365C>A	p.A122D	missense	1	VUS	0.000000
206.	c.1999_2000delinsG	p.Leu667AspfsX15	frameshift	1	Pathogenic	0.000000
207.	c.701C>A	p.T234N	missense	1	Likely Pathogenic	0.000000
208.	c.3676C>T	p.R1226C	missense	1	VUS	0.000058
209.	c.1624+1G>A		essential splice site	1	Pathogenic	0.000000
210.	c.2249C>T	p.T750M	missense	1	Likely Pathogenic	0.000024
211.	c.1090+2T>C		essential splice site	1	Pathogenic	0.000000
212.	c.1213A>G	p.M405V	missense	1	VUS	0.000000
213.	c.211_212delinsTA	p.Val71*	frameshift	1	Pathogenic	0.000000
214.	c.2968C>G	p.P990A	missense	1	Likely Pathogenic	0.000000
215.	c.1377delC		frameshift	1	Pathogenic	0.000000
216.	c.2584C>T	p.Q862X	nonsense	1	Pathogenic	0.000000
217.	c.3316del	p.Asp1106Thrfs*83	frameshift	1	Pathogenic	0.000000
218.	c.2738-2A>G		essential splice site	1	Pathogenic	0.000000
219.	c.2603-2_2603-1delinsGA		essential splice site	1	Pathogenic	0.000000
220.	c.1090+1G>A		essential splice site	1	Pathogenic	0.000000
221.	c.1405C>T	p.Q469X	nonsense	1	Pathogenic	0.000000
222.	c.2502del	p.Arg835Alafs*2	frameshift	1	Pathogenic	0.000000
223.	c.1756C>G	p.P586A	missense	1	Likely Pathogenic	0.000000
224.	c.1457G>A	p.W486X	nonsense	1	Pathogenic	0.000000
225.	c.1266_1267insTGAT	p.Ile423*	frameshift	1	Pathogenic	0.000000
226.	c.3614G>A	p.R1205Q	missense	1	VUS	0.000016
227.	c.3572C>T	p.S1191L	missense	1	VUS	0.000016
228.	c.1072G>A	p.D358N	missense	1	VUS	0.000008
229.	c.3316G>A	p.D1106N	missense	1	VUS	0.000061
230.	c.2304_2308+2delCATCGGT		essential splice site	1	Pathogenic	0.000000
231.	c.821+1G>A		essential splice site	1	Pathogenic	0.000043
232.	c.2504G>T	p.R835L	missense	1	Likely Pathogenic	0.000074
233.	c.982delG		frameshift	1	Pathogenic	0.000000
234.	c.711C>A	p.Y237X	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.