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