MYBPC3 protein-altering 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.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.821+2T>C		essential splice site	4	Pathogenic	0.000000
26.	c.442G>A	p.G148R	missense	4	Likely Pathogenic	0.000042
27.	c.3798C>G	p.C1266W	missense	4	VUS	0.000000
28.	c.3163A>T	p.K1055X	nonsense	4	Pathogenic	0.000000
29.	c.3697C>T	p.Q1233X	nonsense	4	Likely Pathogenic	0.000008
30.	c.2556_2557delinsTCT	p.Gly853fs	frameshift	4	Pathogenic	0.000000
31.	c.1484G>A	p.R495Q	missense	4	Likely Pathogenic	0.000008
32.	c.484C>T	p.Q162X	nonsense	4	Pathogenic	0.000000
33.	c.1720C>T	p.R574W	missense	3	VUS	0.000054
34.	c.3286G>T	p.E1096X	nonsense	3	Pathogenic	0.000000
35.	c.2210C>T	p.T737M	missense	3	VUS	0.000050
36.	c.3129C>A	p.Y1043X	nonsense	3	Pathogenic	0.000000
37.	c.2309-1G>A		essential splice site	3	Pathogenic	0.000000
38.	c.2905+1G>A		essential splice site	3	Pathogenic	0.000000
39.	c.1123G>A	p.V375M	missense	3	VUS	0.000009
40.	c.3763G>A	p.A1255T	missense	3	VUS	0.000075
41.	c.3408C>A	p.Y1136X	nonsense	3	Pathogenic	0.000000
42.	c.3600_3609delCTGCTGTGCT		frameshift	3	Pathogenic	0.000000
43.	c.3277G>T	p.G1093C	missense	3	VUS	0.000020
44.	c.2545del	p.Val849Serfs*30	frameshift	3	Pathogenic	0.000000
45.	c.710A>C	p.Y237S	missense	3	Likely Pathogenic	0.000000
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.1505G>A	p.R502Q	missense	2	Pathogenic	0.000000
50.	c.3752A>G	p.Y1251C	missense	2	VUS	0.000000
51.	c.3005G>A	p.R1002Q	missense	2	VUS	0.000046
52.	c.3627+1G>T		essential splice site	2	Pathogenic	0.000000
53.	c.126G>A	p.W42X	nonsense	2	Pathogenic	0.000000
54.	c.2905+2dup		essential splice site	2	Likely Pathogenic	0.000000
55.	c.2524dup	p.Tyr842Leufs*42	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.3271del	p.Asp1091Metfs*98	frameshift	2	Pathogenic	0.000000
59.	c.177_187del	p.Glu60AlafsX49	frameshift	2	Pathogenic	0.000000
60.	c.3455_3466del	p.Ala1152_Lys1155del	inframe	2	Likely Pathogenic	0.000000
61.	c.557C>T	p.P186L	missense	2	VUS	0.000047
62.	c.443dup	p.Ala149Serfs*4	frameshift	2	Pathogenic	0.000000
63.	c.2308+1G>A		essential splice site	2	Pathogenic	0.000000
64.	c.2219G>C	p.G740A	missense	2	VUS	0.000000
65.	c.747C>A	p.C249X	nonsense	2	Pathogenic	0.000000
66.	c.25+1G>A		essential splice site	2	Pathogenic	0.000000
67.	c.3751T>C	p.Y1251H	missense	2	VUS	0.000000
68.	c.3582_3593delGGGCTACACTGC		inframe	2	Likely Pathogenic	0.000000
69.	c.2526C>G	p.Y842X	nonsense	2	Pathogenic	0.000000
70.	c.1886T>C	p.L629P	missense	2	VUS	0.000000
71.	c.833delG	p.Gly278GlufsX22	frameshift	2	Pathogenic	0.000000
72.	c.2573G>A	p.S858N	missense	2	Likely Pathogenic	0.000000
73.	c.818G>A	p.R273H	missense	2	VUS	0.000042
74.	c.3470C>T	p.P1157L	missense	2	VUS	0.000093
75.	c.2905C>T	p.Q969X	nonsense	2	Pathogenic	0.000000
76.	c.2065C>T	p.Q689X	nonsense	1	Pathogenic	0.000000
77.	c.1352_1353del	p.Glu451Alafs*23	frameshift	1	Pathogenic	0.000000
78.	c.2030C>T	p.P677L	missense	1	VUS	0.000000
79.	c.1458G>A	p.W486X	nonsense	1	Pathogenic	0.000000
80.	c.1456T>G	p.W486G	missense	1	VUS	0.000000
81.	c.1303C>T	p.Q435X	nonsense	1	Pathogenic	0.000000
82.	c.994G>A	p.E332K	missense	1	VUS	0.000009
83.	c.743_746delACTG		frameshift	1	Pathogenic	0.000000
84.	c.1112C>T	p.P371L	missense	1	VUS	0.000028
85.	c.1174G>T	p.A392S	missense	1	VUS	0.000000
86.	c.148A>G	p.S50G	missense	1	VUS	0.000038
87.	c.772+1G>A		essential splice site	1	Pathogenic	0.000000
88.	c.3624delC		frameshift	1	Pathogenic	0.000000
89.	c.3713T>C	p.L1238P	missense	1	Likely Pathogenic	0.000000
90.	c.100_110dup	p.Val38Serfs*5	frameshift	1	Pathogenic	0.000000
91.	c.1038_1042dupCGGCA		frameshift	1	Pathogenic	0.000008
92.	c.2807dup	p.Ala938Glyfs*113	frameshift	1	Pathogenic	0.000000
93.	c.256_258del	p.Ser86del	inframe	1	VUS	0.000000
94.	c.3206C>A	p.P1069H	missense	1	Likely Pathogenic	0.000000
95.	c.3605delG		frameshift	1	Pathogenic	0.000000
96.	c.611_618delinsT	p.Gly204Valfs*94	frameshift	1	Pathogenic	0.000000
97.	c.3357C>A	p.Y1119X	nonsense	1	Pathogenic	0.000000
98.	c.3064C>T	p.R1022C	missense	1	VUS	0.000008
99.	c.2718_2719dup	p.Glu907Glyfs*18	frameshift	1	Pathogenic	0.000000
100.	c.2371C>T	p.Q791X	nonsense	1	Pathogenic	0.000000
101.	c.2909G>A	p.R970Q	missense	1	Likely Pathogenic	0.000032
102.	c.2534_2538delGCGTC		frameshift	1	Pathogenic	0.000000
103.	c.1841A>G	p.Y614C	missense	1	VUS	0.000000
104.	c.1376_1377del	p.Pro459Leufs*15	frameshift	1	Pathogenic	0.000000
105.	c.2449C>T	p.R817W	missense	1	VUS	0.000000
106.	c.2381C>A	p.P794Q	missense	1	VUS	0.000000
107.	c.2197C>T	p.R733C	missense	1	Likely Pathogenic	0.000085
108.	c.1569dup	p.His524Alafs*7	frameshift	1	Pathogenic	0.000000
109.	c.2558delG		frameshift	1	Pathogenic	0.000000
110.	c.2161_2168del	p.Thr721Profs*23	frameshift	1	Pathogenic	0.000000
111.	c.1790G>A	p.R597Q	missense	1	VUS	0.000000
112.	c.1224-1G>T		essential splice site	1	Pathogenic	0.000000
113.	c.1471G>A	p.V491M	missense	1	VUS	0.000058
114.	c.1153G>A	p.V385M	missense	1	VUS	0.000010
115.	c.844C>T	p.R282W	missense	1	Likely Pathogenic	0.000000
116.	c.1351+1G>A		essential splice site	1	Pathogenic	0.000000
117.	c.1021G>C	p.G341R	missense	1	VUS	0.000000
118.	c.506-1G>A		essential splice site	1	Pathogenic	0.000000
119.	c.932C>A	p.S311X	nonsense	1	Pathogenic	0.000000
120.	c.811_817delTTCCGCC		frameshift	1	Pathogenic	0.000000
121.	c.701C>A	p.T234N	missense	1	Likely Pathogenic	0.000000
122.	c.3257G>A	p.W1086X	nonsense	1	Pathogenic	0.000021
123.	c.3676C>T	p.R1226C	missense	1	VUS	0.000058
124.	c.1090+2T>C		essential splice site	1	Pathogenic	0.000000
125.	c.3452C>T	p.A1151V	missense	1	VUS	0.000078
126.	c.365C>A	p.A122D	missense	1	VUS	0.000000
127.	c.211_212delinsTA	p.Val71*	frameshift	1	Pathogenic	0.000000
128.	c.2953A>T	p.K985X	nonsense	1	Pathogenic	0.000000
129.	c.2968C>G	p.P990A	missense	1	Likely Pathogenic	0.000000
130.	c.2584C>T	p.Q862X	nonsense	1	Pathogenic	0.000000
131.	c.3316del	p.Asp1106Thrfs*83	frameshift	1	Pathogenic	0.000000
132.	c.2738-2A>G		essential splice site	1	Pathogenic	0.000000
133.	c.2603-2_2603-1delinsGA		essential splice site	1	Pathogenic	0.000000
134.	c.2873C>T	p.T958I	missense	1	VUS	0.000065
135.	c.1405C>T	p.Q469X	nonsense	1	Pathogenic	0.000000
136.	c.2503C>T	p.R835C	missense	1	VUS	0.000024
137.	c.2502del	p.Arg835Alafs*2	frameshift	1	Pathogenic	0.000000
138.	c.1756C>G	p.P586A	missense	1	Likely Pathogenic	0.000000
139.	c.1457G>A	p.W486X	nonsense	1	Pathogenic	0.000000
140.	c.1685C>T	p.A562V	missense	1	VUS	0.000008
141.	c.2265C>A	p.N755K	missense	1	Pathogenic	0.000000
142.	c.1266_1267insTGAT	p.Ile423*	frameshift	1	Pathogenic	0.000000
143.	c.1433C>T	p.S478L	missense	1	Likely Pathogenic	0.000017
144.	c.1072G>A	p.D358N	missense	1	VUS	0.000008
145.	c.1273C>T	p.Q425X	nonsense	1	Pathogenic	0.000000
146.	c.821+1G>A		essential splice site	1	Pathogenic	0.000043
147.	c.982delG		frameshift	1	Pathogenic	0.000000
148.	c.711C>A	p.Y237X	nonsense	1	Pathogenic	0.000000
149.	c.1090+1G>T		essential splice site	1	Pathogenic	0.000000
150.	c.631G>A	p.D211N	missense	1	VUS	0.000009
151.	c.1120C>T	p.Q374X	nonsense	1	Pathogenic	0.000000
152.	c.3490+1G>A		essential splice site	1	Pathogenic	0.000000
153.	c.49C>T	p.R17W	missense	1	VUS	0.000023
154.	c.3617delG		frameshift	1	Pathogenic	0.000000
155.	c.373G>T	p.A125S	missense	1	VUS	0.000000
156.	c.3728C>G	p.P1243R	missense	1	VUS	0.000000
157.	c.553_562del	p.Lys185Trpfs*12	frameshift	1	Pathogenic	0.000000
158.	c.3334_3351del	p.Trp1112_Glu1117del	inframe	1	Likely Pathogenic	0.000000
159.	c.1021_1028del	p.Gly341*	frameshift	1	Pathogenic	0.000000
160.	c.2789del	p.Leu930Argfs*2	frameshift	1	Pathogenic	0.000000
161.	c.3373G>A	p.V1125M	missense	1	VUS	0.000022
162.	c.255del	p.Ser86Profs*10	frameshift	1	Pathogenic	0.000000
163.	c.2995-1G>A		essential splice site	1	Pathogenic	0.000000
164.	c.2512dup	p.Glu838Glyfs*46	frameshift	1	Pathogenic	0.000000
165.	c.3019T>C	p.W1007R	missense	1	VUS	0.000000
166.	c.2708G>A	p.G903D	missense	1	Likely Pathogenic	0.000000
167.	c.121dup	p.Arg41Profs*8	frameshift	1	Pathogenic	0.000000
168.	c.2834G>A	p.R945Q	missense	1	VUS	0.000000
169.	c.2054_2067+11del	p.Lys685Argfs*3	frameshift	1	Pathogenic	0.000000
170.	c.1828G>C	p.D610H	missense	1	VUS	0.000058
171.	c.1359del	p.Val454Cysfs*12	frameshift	1	Pathogenic	0.000000
172.	c.1523_1525delinsT	p.Gln508Leufs*22	frameshift	1	Pathogenic	0.000000
173.	c.2269G>A	p.V757M	missense	1	VUS	0.000066
174.	c.1591G>A	p.G531R	missense	1	Likely Pathogenic	0.000017
175.	c.1291G>A	p.D431N	missense	1	VUS	0.000028
176.	c.1789C>T	p.R597W	missense	1	VUS	0.000038
177.	c.1223+2T>C		essential splice site	1	Pathogenic	0.000000
178.	c.1898-1G>A		essential splice site	1	Pathogenic	0.000000
179.	c.1021G>A	p.G341S	missense	1	VUS	0.000025
180.	c.459delC		frameshift	1	Pathogenic	0.000000
181.	c.1201C>T	p.Q401X	nonsense	1	Pathogenic	0.000000
182.	c.146_148delTCA	p.Ile49del	inframe	1	VUS	0.000039
183.	c.799C>G	p.L267V	missense	1	VUS	0.000080
184.	c.3792_3793del	p.Cys1264*	frameshift	1	Likely Pathogenic	0.000000
185.	c.351_352del	p.Gly118Argfs*8	frameshift	1	Pathogenic	0.000000
186.	c.3256T>C	p.W1086R	missense	1	VUS	0.000000
187.	c.187C>T	p.R63W	missense	1	VUS	0.000077
188.	c.655-2del		essential splice site	1	Pathogenic	0.000000
189.	c.3253G>T	p.E1085X	nonsense	1	Pathogenic	0.000000
190.	c.3364A>T	p.T1122S	missense	1	Likely Pathogenic	0.000000
191.	c.3656T>C	p.L1219P	missense	1	VUS	0.000000
192.	c.1080G>C	p.K360N	missense	1	VUS	0.000000
193.	c.2149_2737del	p.Leu717Alafs*11	frameshift	1	Pathogenic	0.000000
194.	c.177dup	p.Glu60Argfs*53	frameshift	1	Pathogenic	0.000000
195.	c.2953A>G	p.K985E	missense	1	Pathogenic	0.000000
196.	c.391dup	p.Ala131Glyfs*22	frameshift	1	Pathogenic	0.000000
197.	c.3297dup	p.Tyr1100Valfs*49	frameshift	1	Pathogenic	0.000000
198.	c.2198G>A	p.R733H	missense	1	VUS	0.000034
199.	c.1731G>C	p.W577C	missense	1	VUS	0.000000
200.	c.2188del	p.Thr730Profs*24	frameshift	1	Pathogenic	0.000000
201.	c.1404del	p.Gln469Serfs*19	frameshift	1	Pathogenic	0.000000
202.	c.1231A>G	p.I411V	missense	1	VUS	0.000000
203.	c.1999_2000delinsG	p.Leu667AspfsX15	frameshift	1	Pathogenic	0.000000
204.	c.1455A>T	p.K485N	missense	1	VUS	0.000000
205.	c.1624+1G>A		essential splice site	1	Pathogenic	0.000000
206.	c.2249C>T	p.T750M	missense	1	Likely Pathogenic	0.000024
207.	c.1213A>G	p.M405V	missense	1	VUS	0.000000
208.	c.1377delC		frameshift	1	Pathogenic	0.000000
209.	c.1037G>A	p.R346H	missense	1	VUS	0.000000
210.	c.3811C>T	p.R1271X	nonsense	1	VUS	0.000025
211.	c.1090+1G>A		essential splice site	1	Pathogenic	0.000000
212.	c.532G>A	p.V178M	missense	1	VUS	0.000020
213.	c.731del	p.Lys244Argfs*56	frameshift	1	Pathogenic	0.000000
214.	c.3614G>C	p.R1205P	missense	1	Likely Pathogenic	0.000000
215.	c.1097A>C	p.Q366P	missense	1	VUS	0.000000
216.	c.*26+2T>C		essential splice site	1	Likely Pathogenic	0.000000
217.	c.3614G>A	p.R1205Q	missense	1	VUS	0.000016
218.	c.188G>A	p.R63Q	missense	1	VUS	0.000039
219.	c.3043dup	p.Ala1015Glyfs*36	frameshift	1	Pathogenic	0.000000
220.	c.3572C>T	p.S1191L	missense	1	VUS	0.000016
221.	c.2603-1G>C		essential splice site	1	Pathogenic	0.000000
222.	c.3330+1G>C		essential splice site	1	Pathogenic	0.000000
223.	c.1A>T	p.Met1?	missense	1	Likely Pathogenic	0.000000
224.	c.821+2T>G		essential splice site	1	Pathogenic	0.000000
225.	c.2748G>A	p.W916X	nonsense	1	Pathogenic	0.000000
226.	c.3316G>A	p.D1106N	missense	1	VUS	0.000061
227.	c.3739G>A	p.D1247N	missense	1	VUS	0.000000
228.	c.241G>T	p.V81F	missense	1	VUS	0.000000
229.	c.2304_2308+2delCATCGGT		essential splice site	1	Pathogenic	0.000000
230.	c.2247C>A	p.Y749X	nonsense	1	Pathogenic	0.000000
231.	c.2504G>T	p.R835L	missense	1	Likely Pathogenic	0.000074
232.	c.2429_2503delins23	p.Arg810Profs*10	frameshift	1	Pathogenic	0.000000
233.	c.1797del	p.His599Glnfs*3	frameshift	1	Pathogenic	0.000000
234.	c.2690_2696del	p.Gly897Glufs*25	frameshift	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.