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