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.710A>C	p.Y237S	missense	3	Likely Pathogenic	0.000000
2.	c.818G>A	p.R273H	missense	2	VUS	0.000042
3.	c.532G>A	p.V178M	missense	1	VUS	0.000020
4.	c.3614G>A	p.R1205Q	missense	1	VUS	0.000016
5.	c.188G>A	p.R63Q	missense	1	VUS	0.000039
6.	c.3614G>C	p.R1205P	missense	1	Likely Pathogenic	0.000000
7.	c.3470C>T	p.P1157L	missense	2	VUS	0.000093
8.	c.3572C>T	p.S1191L	missense	1	VUS	0.000016
9.	c.3316G>A	p.D1106N	missense	1	VUS	0.000061
10.	c.3739G>A	p.D1247N	missense	1	VUS	0.000000
11.	c.2504G>T	p.R835L	missense	1	Likely Pathogenic	0.000074
12.	c.2030C>T	p.P677L	missense	1	VUS	0.000000
13.	c.1720C>T	p.R574W	missense	3	VUS	0.000054
14.	c.1828G>A	p.D610N	missense	2	VUS	0.000000
15.	c.2432A>G	p.K811R	missense	2	VUS	0.000000
16.	c.1456T>G	p.W486G	missense	1	VUS	0.000000
17.	c.1505G>A	p.R502Q	missense	2	Pathogenic	0.000000
18.	c.994G>A	p.E332K	missense	1	VUS	0.000009
19.	c.1112C>T	p.P371L	missense	1	VUS	0.000028
20.	c.148A>G	p.S50G	missense	1	VUS	0.000038
21.	c.442G>A	p.G148R	missense	4	Likely Pathogenic	0.000042
22.	c.3713T>C	p.L1238P	missense	1	Likely Pathogenic	0.000000
23.	c.3752A>G	p.Y1251C	missense	2	VUS	0.000000
24.	c.3005G>A	p.R1002Q	missense	2	VUS	0.000046
25.	c.3206C>A	p.P1069H	missense	1	Likely Pathogenic	0.000000
26.	c.3064C>T	p.R1022C	missense	1	VUS	0.000008
27.	c.2909G>A	p.R970Q	missense	1	Likely Pathogenic	0.000032
28.	c.1841A>G	p.Y614C	missense	1	VUS	0.000000
29.	c.2449C>T	p.R817W	missense	1	VUS	0.000000
30.	c.2381C>A	p.P794Q	missense	1	VUS	0.000000
31.	c.2197C>T	p.R733C	missense	1	Likely Pathogenic	0.000085
32.	c.2300A>G	p.K767R	missense	2	VUS	0.000016
33.	c.1080G>C	p.K360N	missense	1	VUS	0.000000
34.	c.1790G>A	p.R597Q	missense	1	VUS	0.000000
35.	c.1471G>A	p.V491M	missense	1	VUS	0.000058
36.	c.1624G>C	p.E542Q	missense	24	Pathogenic	0.000024
37.	c.1021G>C	p.G341R	missense	1	VUS	0.000000
38.	c.1483C>T	p.R495W	missense	2	Likely Pathogenic	0.000000
39.	c.1153G>A	p.V385M	missense	1	VUS	0.000010
40.	c.844C>T	p.R282W	missense	1	Likely Pathogenic	0.000000
41.	c.3771C>A	p.N1257K	missense	9	Likely Pathogenic	0.000000
42.	c.655G>C	p.V219L	missense	18	Likely Pathogenic	0.000000
43.	c.3613C>T	p.R1205W	missense	10	Likely Pathogenic	0.000016
44.	c.3676C>T	p.R1226C	missense	1	VUS	0.000058
45.	c.557C>T	p.P186L	missense	2	VUS	0.000047
46.	c.3452C>T	p.A1151V	missense	1	VUS	0.000078
47.	c.3798C>G	p.C1266W	missense	4	VUS	0.000000
48.	c.2968C>G	p.P990A	missense	1	Likely Pathogenic	0.000000
49.	c.2210C>T	p.T737M	missense	3	VUS	0.000050
50.	c.1756C>G	p.P586A	missense	1	Likely Pathogenic	0.000000
51.	c.2219G>C	p.G740A	missense	2	VUS	0.000000
52.	c.2873C>T	p.T958I	missense	1	VUS	0.000065
53.	c.2503C>T	p.R835C	missense	1	VUS	0.000024
54.	c.1685C>T	p.A562V	missense	1	VUS	0.000008
55.	c.1097A>C	p.Q366P	missense	1	VUS	0.000000
56.	c.2265C>A	p.N755K	missense	1	Pathogenic	0.000000
57.	c.241G>T	p.V81F	missense	1	VUS	0.000000
58.	c.1433C>T	p.S478L	missense	1	Likely Pathogenic	0.000017
59.	c.1072G>A	p.D358N	missense	1	VUS	0.000008
60.	c.1A>T	p.Met1?	missense	1	Likely Pathogenic	0.000000
61.	c.1504C>T	p.R502W	missense	59	Pathogenic	0.000024
62.	c.3728C>G	p.P1243R	missense	1	VUS	0.000000
63.	c.631G>A	p.D211N	missense	1	VUS	0.000009
64.	c.49C>T	p.R17W	missense	1	VUS	0.000023
65.	c.772G>A	p.E258K	missense	47	Pathogenic	0.000039
66.	c.373G>T	p.A125S	missense	1	VUS	0.000000
67.	c.3373G>A	p.V1125M	missense	1	VUS	0.000022
68.	c.3751T>C	p.Y1251H	missense	2	VUS	0.000000
69.	c.2834G>A	p.R945Q	missense	1	VUS	0.000000
70.	c.3019T>C	p.W1007R	missense	1	VUS	0.000000
71.	c.1886T>C	p.L629P	missense	2	VUS	0.000000
72.	c.2708G>A	p.G903D	missense	1	Likely Pathogenic	0.000000
73.	c.2429G>A	p.R810H	missense	11	VUS	0.000033
74.	c.1174G>T	p.A392S	missense	1	VUS	0.000000
75.	c.2269G>A	p.V757M	missense	1	VUS	0.000066
76.	c.1828G>C	p.D610H	missense	1	VUS	0.000058
77.	c.1591G>A	p.G531R	missense	1	Likely Pathogenic	0.000017
78.	c.1291G>A	p.D431N	missense	1	VUS	0.000028
79.	c.1789C>T	p.R597W	missense	1	VUS	0.000038
80.	c.1021G>A	p.G341S	missense	1	VUS	0.000025
81.	c.1123G>A	p.V375M	missense	3	VUS	0.000009
82.	c.799C>G	p.L267V	missense	1	VUS	0.000080
83.	c.3763G>A	p.A1255T	missense	3	VUS	0.000075
84.	c.3256T>C	p.W1086R	missense	1	VUS	0.000000
85.	c.187C>T	p.R63W	missense	1	VUS	0.000077
86.	c.3364A>T	p.T1122S	missense	1	Likely Pathogenic	0.000000
87.	c.3656T>C	p.L1219P	missense	1	VUS	0.000000
88.	c.3277G>T	p.G1093C	missense	3	VUS	0.000020
89.	c.2953A>G	p.K985E	missense	1	Pathogenic	0.000000
90.	c.3065G>C	p.R1022P	missense	5	Likely Pathogenic	0.000025
91.	c.2459G>A	p.R820Q	missense	5	VUS	0.000016
92.	c.2198G>A	p.R733H	missense	1	VUS	0.000034
93.	c.1731G>C	p.W577C	missense	1	VUS	0.000000
94.	c.2573G>A	p.S858N	missense	2	Likely Pathogenic	0.000000
95.	c.2308G>A	p.D770N	missense	5	Likely Pathogenic	0.000008
96.	c.365C>A	p.A122D	missense	1	VUS	0.000000
97.	c.1231A>G	p.I411V	missense	1	VUS	0.000000
98.	c.1483C>G	p.R495G	missense	10	Likely Pathogenic	0.000000
99.	c.701C>A	p.T234N	missense	1	Likely Pathogenic	0.000000
100.	c.1455A>T	p.K485N	missense	1	VUS	0.000000
101.	c.2249C>T	p.T750M	missense	1	Likely Pathogenic	0.000024
102.	c.1213A>G	p.M405V	missense	1	VUS	0.000000
103.	c.1037G>A	p.R346H	missense	1	VUS	0.000000
104.	c.1484G>A	p.R495Q	missense	4	Likely Pathogenic	0.000008
105.	c.3811C>T	p.R1271X	nonsense	1	VUS	0.000025
106.	c.3181C>T	p.Q1061X	nonsense	3	Pathogenic	0.000016
107.	c.2748G>A	p.W916X	nonsense	1	Pathogenic	0.000000
108.	c.2247C>A	p.Y749X	nonsense	1	Pathogenic	0.000000
109.	c.2905C>T	p.Q969X	nonsense	2	Pathogenic	0.000000
110.	c.1458G>A	p.W486X	nonsense	1	Pathogenic	0.000000
111.	c.1120C>T	p.Q374X	nonsense	1	Pathogenic	0.000000
112.	c.2065C>T	p.Q689X	nonsense	1	Pathogenic	0.000000
113.	c.747C>A	p.C249X	nonsense	2	Pathogenic	0.000000
114.	c.1303C>T	p.Q435X	nonsense	1	Pathogenic	0.000000
115.	c.3357C>A	p.Y1119X	nonsense	1	Pathogenic	0.000000
116.	c.2371C>T	p.Q791X	nonsense	1	Pathogenic	0.000000
117.	c.1201C>T	p.Q401X	nonsense	1	Pathogenic	0.000000
118.	c.932C>A	p.S311X	nonsense	1	Pathogenic	0.000000
119.	c.3257G>A	p.W1086X	nonsense	1	Pathogenic	0.000021
120.	c.2827C>T	p.R943X	nonsense	11	Pathogenic	0.000017
121.	c.3286G>T	p.E1096X	nonsense	3	Pathogenic	0.000000
122.	c.2953A>T	p.K985X	nonsense	1	Pathogenic	0.000000
123.	c.2584C>T	p.Q862X	nonsense	1	Pathogenic	0.000000
124.	c.3163A>T	p.K1055X	nonsense	4	Pathogenic	0.000000
125.	c.1405C>T	p.Q469X	nonsense	1	Pathogenic	0.000000
126.	c.1457G>A	p.W486X	nonsense	1	Pathogenic	0.000000
127.	c.484C>T	p.Q162X	nonsense	4	Pathogenic	0.000000
128.	c.1273C>T	p.Q425X	nonsense	1	Pathogenic	0.000000
129.	c.711C>A	p.Y237X	nonsense	1	Pathogenic	0.000000
130.	c.3697C>T	p.Q1233X	nonsense	4	Likely Pathogenic	0.000008
131.	c.3129C>A	p.Y1043X	nonsense	3	Pathogenic	0.000000
132.	c.2526C>G	p.Y842X	nonsense	2	Pathogenic	0.000000
133.	c.126G>A	p.W42X	nonsense	2	Pathogenic	0.000000
134.	c.3408C>A	p.Y1136X	nonsense	3	Pathogenic	0.000000
135.	c.3253G>T	p.E1085X	nonsense	1	Pathogenic	0.000000
136.	c.1090+1G>A		essential splice site	1	Pathogenic	0.000000
137.	c.*26+2T>C		essential splice site	1	Likely Pathogenic	0.000000
138.	c.2603-1G>C		essential splice site	1	Pathogenic	0.000000
139.	c.3330+1G>C		essential splice site	1	Pathogenic	0.000000
140.	c.2304_2308+2delCATCGGT		essential splice site	1	Pathogenic	0.000000
141.	c.25+1G>A		essential splice site	2	Pathogenic	0.000000
142.	c.821+2T>C		essential splice site	4	Pathogenic	0.000000
143.	c.772+1G>A		essential splice site	1	Pathogenic	0.000000
144.	c.3627+1G>T		essential splice site	2	Pathogenic	0.000000
145.	c.2905+2dup		essential splice site	2	Likely Pathogenic	0.000000
146.	c.1224-1G>T		essential splice site	1	Pathogenic	0.000000
147.	c.655-2del		essential splice site	1	Pathogenic	0.000000
148.	c.1928-2A>G		essential splice site	10	Pathogenic	0.000000
149.	c.1351+1G>A		essential splice site	1	Pathogenic	0.000000
150.	c.506-1G>A		essential splice site	1	Pathogenic	0.000000
151.	c.2738-2A>G		essential splice site	1	Pathogenic	0.000000
152.	c.2603-2_2603-1delinsGA		essential splice site	1	Pathogenic	0.000000
153.	c.2308+1G>A		essential splice site	2	Pathogenic	0.000000
154.	c.821+2T>G		essential splice site	1	Pathogenic	0.000000
155.	c.1090+1G>T		essential splice site	1	Pathogenic	0.000000
156.	c.821+1G>A		essential splice site	1	Pathogenic	0.000043
157.	c.3490+1G>A		essential splice site	1	Pathogenic	0.000000
158.	c.3190+2T>G		essential splice site	7	Pathogenic	0.000016
159.	c.2995-1G>A		essential splice site	1	Pathogenic	0.000000
160.	c.2309-1G>A		essential splice site	3	Pathogenic	0.000000
161.	c.2905+1G>A		essential splice site	3	Pathogenic	0.000000
162.	c.1223+2T>C		essential splice site	1	Pathogenic	0.000000
163.	c.1898-1G>A		essential splice site	1	Pathogenic	0.000000
164.	c.3627+1G>A		essential splice site	6	Pathogenic	0.000000
165.	c.927-2A>G		essential splice site	8	Pathogenic	0.000000
166.	c.1624+1G>A		essential splice site	1	Pathogenic	0.000000
167.	c.1090+2T>C		essential splice site	1	Pathogenic	0.000000
168.	c.3043dup	p.Ala1015Glyfs*36	frameshift	1	Pathogenic	0.000000
169.	c.2864_2865delCT		frameshift	8	Pathogenic	0.000000
170.	c.2429_2503delins23	p.Arg810Profs*10	frameshift	1	Pathogenic	0.000000
171.	c.1797del	p.His599Glnfs*3	frameshift	1	Pathogenic	0.000000
172.	c.2610delC		frameshift	5	Pathogenic	0.000000
173.	c.2690_2696del	p.Gly897Glufs*25	frameshift	1	Pathogenic	0.000000
174.	c.2267delC		frameshift	5	Pathogenic	0.000000
175.	c.1352_1353del	p.Glu451Alafs*23	frameshift	1	Pathogenic	0.000000
176.	c.553_562del	p.Lys185Trpfs*12	frameshift	1	Pathogenic	0.000000
177.	c.1021_1028del	p.Gly341*	frameshift	1	Pathogenic	0.000000
178.	c.255del	p.Ser86Profs*10	frameshift	1	Pathogenic	0.000000
179.	c.743_746delACTG		frameshift	1	Pathogenic	0.000000
180.	c.121dup	p.Arg41Profs*8	frameshift	1	Pathogenic	0.000000
181.	c.3624delC		frameshift	1	Pathogenic	0.000000
182.	c.3226_3227insT		frameshift	12	Pathogenic	0.000000
183.	c.2807dup	p.Ala938Glyfs*113	frameshift	1	Pathogenic	0.000000
184.	c.3605delG		frameshift	1	Pathogenic	0.000000
185.	c.2534_2538delGCGTC		frameshift	1	Pathogenic	0.000000
186.	c.2524dup	p.Tyr842Leufs*42	frameshift	2	Pathogenic	0.000000
187.	c.2718_2719dup	p.Glu907Glyfs*18	frameshift	1	Pathogenic	0.000000
188.	c.1376_1377del	p.Pro459Leufs*15	frameshift	1	Pathogenic	0.000000
189.	c.1569dup	p.His524Alafs*7	frameshift	1	Pathogenic	0.000000
190.	c.2558delG		frameshift	1	Pathogenic	0.000000
191.	c.2161_2168del	p.Thr721Profs*23	frameshift	1	Pathogenic	0.000000
192.	c.351_352del	p.Gly118Argfs*8	frameshift	1	Pathogenic	0.000000
193.	c.177dup	p.Glu60Argfs*53	frameshift	1	Pathogenic	0.000000
194.	c.391dup	p.Ala131Glyfs*22	frameshift	1	Pathogenic	0.000000
195.	c.811_817delTTCCGCC		frameshift	1	Pathogenic	0.000000
196.	c.3271del	p.Asp1091Metfs*98	frameshift	2	Pathogenic	0.000000
197.	c.177_187del	p.Glu60AlafsX49	frameshift	2	Pathogenic	0.000000
198.	c.3316del	p.Asp1106Thrfs*83	frameshift	1	Pathogenic	0.000000
199.	c.2604_2605delinsA	p.S871fs	frameshift	8	Pathogenic	0.000000
200.	c.2502del	p.Arg835Alafs*2	frameshift	1	Pathogenic	0.000000
201.	c.731del	p.Lys244Argfs*56	frameshift	1	Pathogenic	0.000000
202.	c.1266_1267insTGAT	p.Ile423*	frameshift	1	Pathogenic	0.000000
203.	c.982delG		frameshift	1	Pathogenic	0.000000
204.	c.3617delG		frameshift	1	Pathogenic	0.000000
205.	c.2789del	p.Leu930Argfs*2	frameshift	1	Pathogenic	0.000000
206.	c.2512dup	p.Glu838Glyfs*46	frameshift	1	Pathogenic	0.000000
207.	c.2054_2067+11del	p.Lys685Argfs*3	frameshift	1	Pathogenic	0.000000
208.	c.1359del	p.Val454Cysfs*12	frameshift	1	Pathogenic	0.000000
209.	c.2096delC		frameshift	15	Pathogenic	0.000000
210.	c.1523_1525delinsT	p.Gln508Leufs*22	frameshift	1	Pathogenic	0.000000
211.	c.100_110dup	p.Val38Serfs*5	frameshift	1	Pathogenic	0.000000
212.	c.1038_1042dupCGGCA		frameshift	1	Pathogenic	0.000008
213.	c.611_618delinsT	p.Gly204Valfs*94	frameshift	1	Pathogenic	0.000000
214.	c.833delG	p.Gly278GlufsX22	frameshift	2	Pathogenic	0.000000
215.	c.459delC		frameshift	1	Pathogenic	0.000000
216.	c.3792_3793del	p.Cys1264*	frameshift	1	Likely Pathogenic	0.000000
217.	c.3600_3609delCTGCTGTGCT		frameshift	3	Pathogenic	0.000000
218.	c.2149_2737del	p.Leu717Alafs*11	frameshift	1	Pathogenic	0.000000
219.	c.2373_2374insG	p.Trp792ValfsTer41	frameshift	40	Pathogenic	0.000037
220.	c.2556_2557delinsTCT	p.Gly853fs	frameshift	4	Pathogenic	0.000000
221.	c.2545del	p.Val849Serfs*30	frameshift	3	Pathogenic	0.000000
222.	c.3297dup	p.Tyr1100Valfs*49	frameshift	1	Pathogenic	0.000000
223.	c.2490_2491insT	p.His831SerfsTer2	frameshift	7	Pathogenic	0.000024
224.	c.2188del	p.Thr730Profs*24	frameshift	1	Pathogenic	0.000000
225.	c.1404del	p.Gln469Serfs*19	frameshift	1	Pathogenic	0.000000
226.	c.1999_2000delinsG	p.Leu667AspfsX15	frameshift	1	Pathogenic	0.000000
227.	c.211_212delinsTA	p.Val71*	frameshift	1	Pathogenic	0.000000
228.	c.1377delC		frameshift	1	Pathogenic	0.000000
229.	c.443dup	p.Ala149Serfs*4	frameshift	2	Pathogenic	0.000000
230.	c.3455_3466del	p.Ala1152_Lys1155del	inframe	2	Likely Pathogenic	0.000000
231.	c.3334_3351del	p.Trp1112_Glu1117del	inframe	1	Likely Pathogenic	0.000000
232.	c.3582_3593delGGGCTACACTGC		inframe	2	Likely Pathogenic	0.000000
233.	c.256_258del	p.Ser86del	inframe	1	VUS	0.000000
234.	c.146_148delTCA	p.Ile49del	inframe	1	VUS	0.000039

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.