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.2429G>A	p.R810H	missense	11	VUS	0.000033
9.	c.2827C>T	p.R943X	nonsense	11	Pathogenic	0.000017
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.2864_2865delCT		frameshift	8	Pathogenic	0.000000
15.	c.927-2A>G		essential splice site	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.821+2T>C		essential splice site	4	Pathogenic	0.000000
26.	c.442G>A	p.G148R	missense	4	Likely Pathogenic	0.000042
27.	c.2556_2557delinsTCT	p.Gly853fs	frameshift	4	Pathogenic	0.000000
28.	c.3798C>G	p.C1266W	missense	4	VUS	0.000000
29.	c.1484G>A	p.R495Q	missense	4	Likely Pathogenic	0.000008
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.2905+1G>A		essential splice site	3	Pathogenic	0.000000
34.	c.1123G>A	p.V375M	missense	3	VUS	0.000009
35.	c.3763G>A	p.A1255T	missense	3	VUS	0.000075
36.	c.3600_3609delCTGCTGTGCT		frameshift	3	Pathogenic	0.000000
37.	c.3408C>A	p.Y1136X	nonsense	3	Pathogenic	0.000000
38.	c.3277G>T	p.G1093C	missense	3	VUS	0.000020
39.	c.3181C>T	p.Q1061X	nonsense	3	Pathogenic	0.000016
40.	c.1720C>T	p.R574W	missense	3	VUS	0.000054
41.	c.3129C>A	p.Y1043X	nonsense	3	Pathogenic	0.000000
42.	c.2309-1G>A		essential splice site	3	Pathogenic	0.000000
43.	c.2545del	p.Val849Serfs*30	frameshift	3	Pathogenic	0.000000
44.	c.3286G>T	p.E1096X	nonsense	3	Pathogenic	0.000000
45.	c.2210C>T	p.T737M	missense	3	VUS	0.000050
46.	c.710A>C	p.Y237S	missense	3	Likely Pathogenic	0.000000
47.	c.2526C>G	p.Y842X	nonsense	2	Pathogenic	0.000000
48.	c.3752A>G	p.Y1251C	missense	2	VUS	0.000000
49.	c.126G>A	p.W42X	nonsense	2	Pathogenic	0.000000
50.	c.2905+2dup		essential splice site	2	Likely Pathogenic	0.000000
51.	c.2524dup	p.Tyr842Leufs*42	frameshift	2	Pathogenic	0.000000
52.	c.2573G>A	p.S858N	missense	2	Likely Pathogenic	0.000000
53.	c.3455_3466del	p.Ala1152_Lys1155del	inframe	2	Likely Pathogenic	0.000000
54.	c.557C>T	p.P186L	missense	2	VUS	0.000047
55.	c.3271del	p.Asp1091Metfs*98	frameshift	2	Pathogenic	0.000000
56.	c.177_187del	p.Glu60AlafsX49	frameshift	2	Pathogenic	0.000000
57.	c.443dup	p.Ala149Serfs*4	frameshift	2	Pathogenic	0.000000
58.	c.2219G>C	p.G740A	missense	2	VUS	0.000000
59.	c.3470C>T	p.P1157L	missense	2	VUS	0.000093
60.	c.2905C>T	p.Q969X	nonsense	2	Pathogenic	0.000000
61.	c.1828G>A	p.D610N	missense	2	VUS	0.000000
62.	c.2432A>G	p.K811R	missense	2	VUS	0.000000
63.	c.747C>A	p.C249X	nonsense	2	Pathogenic	0.000000
64.	c.1505G>A	p.R502Q	missense	2	Pathogenic	0.000000
65.	c.25+1G>A		essential splice site	2	Pathogenic	0.000000
66.	c.3751T>C	p.Y1251H	missense	2	VUS	0.000000
67.	c.1886T>C	p.L629P	missense	2	VUS	0.000000
68.	c.3005G>A	p.R1002Q	missense	2	VUS	0.000046
69.	c.3627+1G>T		essential splice site	2	Pathogenic	0.000000
70.	c.833delG	p.Gly278GlufsX22	frameshift	2	Pathogenic	0.000000
71.	c.2300A>G	p.K767R	missense	2	VUS	0.000016
72.	c.1483C>T	p.R495W	missense	2	Likely Pathogenic	0.000000
73.	c.2308+1G>A		essential splice site	2	Pathogenic	0.000000
74.	c.818G>A	p.R273H	missense	2	VUS	0.000042
75.	c.3582_3593delGGGCTACACTGC		inframe	2	Likely Pathogenic	0.000000
76.	c.3019T>C	p.W1007R	missense	1	VUS	0.000000
77.	c.994G>A	p.E332K	missense	1	VUS	0.000009
78.	c.743_746delACTG		frameshift	1	Pathogenic	0.000000
79.	c.1828G>C	p.D610H	missense	1	VUS	0.000058
80.	c.2269G>A	p.V757M	missense	1	VUS	0.000066
81.	c.1174G>T	p.A392S	missense	1	VUS	0.000000
82.	c.148A>G	p.S50G	missense	1	VUS	0.000038
83.	c.772+1G>A		essential splice site	1	Pathogenic	0.000000
84.	c.1291G>A	p.D431N	missense	1	VUS	0.000028
85.	c.1789C>T	p.R597W	missense	1	VUS	0.000038
86.	c.256_258del	p.Ser86del	inframe	1	VUS	0.000000
87.	c.3206C>A	p.P1069H	missense	1	Likely Pathogenic	0.000000
88.	c.1898-1G>A		essential splice site	1	Pathogenic	0.000000
89.	c.611_618delinsT	p.Gly204Valfs*94	frameshift	1	Pathogenic	0.000000
90.	c.3357C>A	p.Y1119X	nonsense	1	Pathogenic	0.000000
91.	c.1591G>A	p.G531R	missense	1	Likely Pathogenic	0.000017
92.	c.100_110dup	p.Val38Serfs*5	frameshift	1	Pathogenic	0.000000
93.	c.1038_1042dupCGGCA		frameshift	1	Pathogenic	0.000008
94.	c.2807dup	p.Ala938Glyfs*113	frameshift	1	Pathogenic	0.000000
95.	c.2718_2719dup	p.Glu907Glyfs*18	frameshift	1	Pathogenic	0.000000
96.	c.2371C>T	p.Q791X	nonsense	1	Pathogenic	0.000000
97.	c.1569dup	p.His524Alafs*7	frameshift	1	Pathogenic	0.000000
98.	c.2161_2168del	p.Thr721Profs*23	frameshift	1	Pathogenic	0.000000
99.	c.1376_1377del	p.Pro459Leufs*15	frameshift	1	Pathogenic	0.000000
100.	c.2381C>A	p.P794Q	missense	1	VUS	0.000000
101.	c.1224-1G>T		essential splice site	1	Pathogenic	0.000000
102.	c.3253G>T	p.E1085X	nonsense	1	Pathogenic	0.000000
103.	c.3656T>C	p.L1219P	missense	1	VUS	0.000000
104.	c.844C>T	p.R282W	missense	1	Likely Pathogenic	0.000000
105.	c.1021G>C	p.G341R	missense	1	VUS	0.000000
106.	c.811_817delTTCCGCC		frameshift	1	Pathogenic	0.000000
107.	c.506-1G>A		essential splice site	1	Pathogenic	0.000000
108.	c.932C>A	p.S311X	nonsense	1	Pathogenic	0.000000
109.	c.2198G>A	p.R733H	missense	1	VUS	0.000034
110.	c.1999_2000delinsG	p.Leu667AspfsX15	frameshift	1	Pathogenic	0.000000
111.	c.701C>A	p.T234N	missense	1	Likely Pathogenic	0.000000
112.	c.1624+1G>A		essential splice site	1	Pathogenic	0.000000
113.	c.2249C>T	p.T750M	missense	1	Likely Pathogenic	0.000024
114.	c.1090+2T>C		essential splice site	1	Pathogenic	0.000000
115.	c.365C>A	p.A122D	missense	1	VUS	0.000000
116.	c.2968C>G	p.P990A	missense	1	Likely Pathogenic	0.000000
117.	c.1377delC		frameshift	1	Pathogenic	0.000000
118.	c.2584C>T	p.Q862X	nonsense	1	Pathogenic	0.000000
119.	c.3316del	p.Asp1106Thrfs*83	frameshift	1	Pathogenic	0.000000
120.	c.2738-2A>G		essential splice site	1	Pathogenic	0.000000
121.	c.1213A>G	p.M405V	missense	1	VUS	0.000000
122.	c.211_212delinsTA	p.Val71*	frameshift	1	Pathogenic	0.000000
123.	c.1405C>T	p.Q469X	nonsense	1	Pathogenic	0.000000
124.	c.2502del	p.Arg835Alafs*2	frameshift	1	Pathogenic	0.000000
125.	c.1756C>G	p.P586A	missense	1	Likely Pathogenic	0.000000
126.	c.2603-2_2603-1delinsGA		essential splice site	1	Pathogenic	0.000000
127.	c.3811C>T	p.R1271X	nonsense	1	VUS	0.000025
128.	c.1090+1G>A		essential splice site	1	Pathogenic	0.000000
129.	c.1266_1267insTGAT	p.Ile423*	frameshift	1	Pathogenic	0.000000
130.	c.3614G>A	p.R1205Q	missense	1	VUS	0.000016
131.	c.1457G>A	p.W486X	nonsense	1	Pathogenic	0.000000
132.	c.1072G>A	p.D358N	missense	1	VUS	0.000008
133.	c.3316G>A	p.D1106N	missense	1	VUS	0.000061
134.	c.3572C>T	p.S1191L	missense	1	VUS	0.000016
135.	c.821+1G>A		essential splice site	1	Pathogenic	0.000043
136.	c.2504G>T	p.R835L	missense	1	Likely Pathogenic	0.000074
137.	c.982delG		frameshift	1	Pathogenic	0.000000
138.	c.711C>A	p.Y237X	nonsense	1	Pathogenic	0.000000
139.	c.2304_2308+2delCATCGGT		essential splice site	1	Pathogenic	0.000000
140.	c.1120C>T	p.Q374X	nonsense	1	Pathogenic	0.000000
141.	c.49C>T	p.R17W	missense	1	VUS	0.000023
142.	c.373G>T	p.A125S	missense	1	VUS	0.000000
143.	c.2030C>T	p.P677L	missense	1	VUS	0.000000
144.	c.3728C>G	p.P1243R	missense	1	VUS	0.000000
145.	c.631G>A	p.D211N	missense	1	VUS	0.000009
146.	c.1021_1028del	p.Gly341*	frameshift	1	Pathogenic	0.000000
147.	c.2789del	p.Leu930Argfs*2	frameshift	1	Pathogenic	0.000000
148.	c.255del	p.Ser86Profs*10	frameshift	1	Pathogenic	0.000000
149.	c.1456T>G	p.W486G	missense	1	VUS	0.000000
150.	c.553_562del	p.Lys185Trpfs*12	frameshift	1	Pathogenic	0.000000
151.	c.3334_3351del	p.Trp1112_Glu1117del	inframe	1	Likely Pathogenic	0.000000
152.	c.2512dup	p.Glu838Glyfs*46	frameshift	1	Pathogenic	0.000000
153.	c.2708G>A	p.G903D	missense	1	Likely Pathogenic	0.000000
154.	c.1112C>T	p.P371L	missense	1	VUS	0.000028
155.	c.121dup	p.Arg41Profs*8	frameshift	1	Pathogenic	0.000000
156.	c.2834G>A	p.R945Q	missense	1	VUS	0.000000
157.	c.1303C>T	p.Q435X	nonsense	1	Pathogenic	0.000000
158.	c.1359del	p.Val454Cysfs*12	frameshift	1	Pathogenic	0.000000
159.	c.3624delC		frameshift	1	Pathogenic	0.000000
160.	c.1523_1525delinsT	p.Gln508Leufs*22	frameshift	1	Pathogenic	0.000000
161.	c.3713T>C	p.L1238P	missense	1	Likely Pathogenic	0.000000
162.	c.2054_2067+11del	p.Lys685Argfs*3	frameshift	1	Pathogenic	0.000000
163.	c.1223+2T>C		essential splice site	1	Pathogenic	0.000000
164.	c.3605delG		frameshift	1	Pathogenic	0.000000
165.	c.2909G>A	p.R970Q	missense	1	Likely Pathogenic	0.000032
166.	c.2534_2538delGCGTC		frameshift	1	Pathogenic	0.000000
167.	c.3064C>T	p.R1022C	missense	1	VUS	0.000008
168.	c.1021G>A	p.G341S	missense	1	VUS	0.000025
169.	c.459delC		frameshift	1	Pathogenic	0.000000
170.	c.2197C>T	p.R733C	missense	1	Likely Pathogenic	0.000085
171.	c.2558delG		frameshift	1	Pathogenic	0.000000
172.	c.1201C>T	p.Q401X	nonsense	1	Pathogenic	0.000000
173.	c.146_148delTCA	p.Ile49del	inframe	1	VUS	0.000039
174.	c.799C>G	p.L267V	missense	1	VUS	0.000080
175.	c.1841A>G	p.Y614C	missense	1	VUS	0.000000
176.	c.2449C>T	p.R817W	missense	1	VUS	0.000000
177.	c.351_352del	p.Gly118Argfs*8	frameshift	1	Pathogenic	0.000000
178.	c.3256T>C	p.W1086R	missense	1	VUS	0.000000
179.	c.187C>T	p.R63W	missense	1	VUS	0.000077
180.	c.1471G>A	p.V491M	missense	1	VUS	0.000058
181.	c.655-2del		essential splice site	1	Pathogenic	0.000000
182.	c.3364A>T	p.T1122S	missense	1	Likely Pathogenic	0.000000
183.	c.1080G>C	p.K360N	missense	1	VUS	0.000000
184.	c.3792_3793del	p.Cys1264*	frameshift	1	Likely Pathogenic	0.000000
185.	c.1790G>A	p.R597Q	missense	1	VUS	0.000000
186.	c.1153G>A	p.V385M	missense	1	VUS	0.000010
187.	c.177dup	p.Glu60Argfs*53	frameshift	1	Pathogenic	0.000000
188.	c.2953A>G	p.K985E	missense	1	Pathogenic	0.000000
189.	c.1351+1G>A		essential splice site	1	Pathogenic	0.000000
190.	c.391dup	p.Ala131Glyfs*22	frameshift	1	Pathogenic	0.000000
191.	c.3297dup	p.Tyr1100Valfs*49	frameshift	1	Pathogenic	0.000000
192.	c.2149_2737del	p.Leu717Alafs*11	frameshift	1	Pathogenic	0.000000
193.	c.1731G>C	p.W577C	missense	1	VUS	0.000000
194.	c.2188del	p.Thr730Profs*24	frameshift	1	Pathogenic	0.000000
195.	c.1404del	p.Gln469Serfs*19	frameshift	1	Pathogenic	0.000000
196.	c.3257G>A	p.W1086X	nonsense	1	Pathogenic	0.000021
197.	c.1455A>T	p.K485N	missense	1	VUS	0.000000
198.	c.3676C>T	p.R1226C	missense	1	VUS	0.000058
199.	c.3452C>T	p.A1151V	missense	1	VUS	0.000078
200.	c.1231A>G	p.I411V	missense	1	VUS	0.000000
201.	c.1037G>A	p.R346H	missense	1	VUS	0.000000
202.	c.2953A>T	p.K985X	nonsense	1	Pathogenic	0.000000
203.	c.2873C>T	p.T958I	missense	1	VUS	0.000065
204.	c.2503C>T	p.R835C	missense	1	VUS	0.000024
205.	c.532G>A	p.V178M	missense	1	VUS	0.000020
206.	c.3614G>C	p.R1205P	missense	1	Likely Pathogenic	0.000000
207.	c.1685C>T	p.A562V	missense	1	VUS	0.000008
208.	c.2265C>A	p.N755K	missense	1	Pathogenic	0.000000
209.	c.1097A>C	p.Q366P	missense	1	VUS	0.000000
210.	c.*26+2T>C		essential splice site	1	Likely Pathogenic	0.000000
211.	c.188G>A	p.R63Q	missense	1	VUS	0.000039
212.	c.731del	p.Lys244Argfs*56	frameshift	1	Pathogenic	0.000000
213.	c.2603-1G>C		essential splice site	1	Pathogenic	0.000000
214.	c.3330+1G>C		essential splice site	1	Pathogenic	0.000000
215.	c.1A>T	p.Met1?	missense	1	Likely Pathogenic	0.000000
216.	c.821+2T>G		essential splice site	1	Pathogenic	0.000000
217.	c.2748G>A	p.W916X	nonsense	1	Pathogenic	0.000000
218.	c.3739G>A	p.D1247N	missense	1	VUS	0.000000
219.	c.1273C>T	p.Q425X	nonsense	1	Pathogenic	0.000000
220.	c.241G>T	p.V81F	missense	1	VUS	0.000000
221.	c.3043dup	p.Ala1015Glyfs*36	frameshift	1	Pathogenic	0.000000
222.	c.1433C>T	p.S478L	missense	1	Likely Pathogenic	0.000017
223.	c.2429_2503delins23	p.Arg810Profs*10	frameshift	1	Pathogenic	0.000000
224.	c.1797del	p.His599Glnfs*3	frameshift	1	Pathogenic	0.000000
225.	c.2690_2696del	p.Gly897Glufs*25	frameshift	1	Pathogenic	0.000000
226.	c.1090+1G>T		essential splice site	1	Pathogenic	0.000000
227.	c.2247C>A	p.Y749X	nonsense	1	Pathogenic	0.000000
228.	c.3490+1G>A		essential splice site	1	Pathogenic	0.000000
229.	c.2065C>T	p.Q689X	nonsense	1	Pathogenic	0.000000
230.	c.1352_1353del	p.Glu451Alafs*23	frameshift	1	Pathogenic	0.000000
231.	c.3617delG		frameshift	1	Pathogenic	0.000000
232.	c.1458G>A	p.W486X	nonsense	1	Pathogenic	0.000000
233.	c.3373G>A	p.V1125M	missense	1	VUS	0.000022
234.	c.2995-1G>A		essential splice site	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.