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