MYBPC3 variants in HCM cohorts

The table below lists the 540 rare (MAF<0.0001 in ExAC) protein-altering MYBPC3 variants identified in a cohort of 2912 HCM patients. When this rare variant frequency of 0.18544 is compared with a background population rate of 0.01970, there is a statistically significant case excess of 0.16574 (p<0.0001), which suggests that approximately 481 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 (2912)▼	LMM class	ExAC frequency
1.	c.1504C>T	p.R502W	missense	45	Pathogenic	0.000024
2.	c.2373_2374insG	p.Trp792ValfsTer41	frameshift	26	Pathogenic	0.000037
3.	c.772G>A	p.E258K	missense	21	Pathogenic	0.000039
4.	c.1928-2A>G		essential splice site	20	Pathogenic	0.000000
5.	c.1624G>C	p.E542Q	missense	17	Likely Pathogenic	0.000024
6.	c.3330+2T>G		essential splice site	11	Pathogenic	0.000000
7.	c.1484G>A	p.R495Q	missense	10	VUS favour pathogenic	0.000008
8.	c.2309-2A>G		essential splice site	9	Pathogenic	0.000000
9.	c.3697C>T	p.Q1233X	nonsense	9	Pathogenic	0.000008
10.	c.2429G>A	p.R810H	missense	8	VUS favour pathogenic	0.000033
11.	c.655G>C	p.V219L	missense	8	Likely Pathogenic	0.000000
12.	c.2670G>A	p.W890X	nonsense	7	Pathogenic	0.000000
13.	c.442G>A	p.G148R	missense	7	VUS favour pathogenic	0.000042
14.	c.2827C>T	p.R943X	nonsense	7	Pathogenic	0.000017
15.	c.1505G>A	p.R502Q	missense	6	Pathogenic	0.000000
16.	c.3226_3227insT		frameshift	6	Pathogenic	0.000000
17.	c.2864_2865delCT		frameshift	6	Pathogenic	0.000000
18.	c.2308G>A	p.D770N	missense	6	Likely Pathogenic	0.000008
19.	c.2374T>C	p.W792R	missense	5	Likely Pathogenic	0.000000
20.	c.913_914delTT		frameshift	5	Pathogenic	0.000000
21.	c.821+1G>A		essential splice site	4	Pathogenic	0.000043
22.	c.2905+1G>A		essential splice site	4	Pathogenic	0.000000
23.	c.3742_3759dup	p.Gly1248_Cys1253dup	inframe	4	Likely Pathogenic	0.000000
24.	c.2454G>A	p.W818X	nonsense	4	Pathogenic	0.000000
25.	c.3064C>T	p.R1022C	missense	4	VUS favour pathogenic	0.000008
26.	c.2096delC		frameshift	4	Pathogenic	0.000000
27.	c.1483C>G	p.R495G	missense	4	Likely Pathogenic	0.000000
28.	c.2573G>A	p.S858N	missense	4	VUS favour pathogenic	0.000000
29.	c.2182G>T	p.E728X	nonsense	4	Pathogenic	0.000000
30.	c.26-2A>G		essential splice site	4	Pathogenic	0.000051
31.	c.3491-2A>T		essential splice site	3	Pathogenic	0.000000
32.	c.2873C>T	p.T958I	missense	3	VUS favour benign	0.000065
33.	c.2311_2312insG	p.Val771GlyfsX62	frameshift	3	Pathogenic	0.000000
34.	c.1591G>A	p.G531R	missense	3	VUS favour pathogenic	0.000017
35.	c.3767_3769delCCA	p.Thr1256del	inframe	3	Likely Pathogenic	0.000000
36.	c.1828G>A	p.D610N	missense	3	VUS	0.000000
37.	c.710A>C	p.Y237S	missense	3	Likely Pathogenic	0.000000
38.	c.2450G>A	p.R817Q	missense	3	VUS favour pathogenic	0.000016
39.	c.3233G>A	p.W1078X	nonsense	3	Pathogenic	0.000022
40.	c.3190+1G>A		essential splice site	3	Pathogenic	0.000000
41.	c.2920C>T	p.Q974X	nonsense	3	Pathogenic	0.000000
42.	c.355G>A	p.E119K	missense	3	VUS	0.000000
43.	c.2905C>T	p.Q969X	nonsense	3	Pathogenic	0.000000
44.	c.636C>G	p.S212R	missense	2	VUS favour pathogenic	0.000000
45.	c.1897+1G>A		essential splice site	2	Pathogenic	0.000000
46.	c.1828G>C	p.D610H	missense	2	VUS favour benign	0.000058
47.	c.1357_1358delCC		frameshift	2	Pathogenic	0.000000
48.	c.1863delC	p.Phe621LeufsX42	frameshift	2	Pathogenic	0.000000
49.	c.3192_3193insC	p.Lys1065GlnfsX12	frameshift	2	Pathogenic	0.000000
50.	c.1790G>A	p.R597Q	missense	2	VUS favour pathogenic	0.000000
51.	c.1483C>T	p.R495W	missense	2	VUS favour pathogenic	0.000000
52.	c.3624_3625insC	p.Lys1209GlnfsX33	frameshift	2	Pathogenic	0.000000
53.	c.2943_2947delGACCA		frameshift	2	Pathogenic	0.000000
54.	c.999C>G	p.Y333X	nonsense	2	Pathogenic	0.000000
55.	c.1766G>A	p.R589H	missense	2	VUS	0.000000
56.	c.927-2A>G		essential splice site	2	Pathogenic	0.000000
57.	c.2558delG		frameshift	2	Pathogenic	0.000000
58.	c.1895delT	p.Met632ArgfsX31	frameshift	2	Pathogenic	0.000000
59.	c.2882C>T	p.P961L	missense	2	VUS	0.000048
60.	c.1037G>A	p.R346H	missense	2	VUS	0.000000
61.	c.772+1G>A		essential splice site	2	Pathogenic	0.000000
62.	c.3627+1G>A		essential splice site	2	Pathogenic	0.000000
63.	c.2604_2605delinsA	p.S871fs	frameshift	2	Pathogenic	0.000000
64.	c.532G>A	p.V178M	missense	2	VUS favour pathogenic	0.000020
65.	c.1210C>T	p.Q404X	nonsense	2	Pathogenic	0.000000
66.	c.3190+2T>G		essential splice site	2	Pathogenic	0.000016
67.	c.436_437insA	p.Thr146AsnfsX7	frameshift	2	Pathogenic	0.000000
68.	c.1869C>A	p.C623X	nonsense	2	Pathogenic	0.000000
69.	c.3624delC		frameshift	2	Pathogenic	0.000000
70.	c.1934C>T	p.P645L	missense	2	VUS	0.000000
71.	c.814C>T	p.R272C	missense	2	VUS	0.000083
72.	c.2320G>A	p.A774T	missense	2	VUS	0.000000
73.	c.1513_1515delAAG		inframe	2	VUS favour pathogenic	0.000000
74.	c.1456T>G	p.W486G	missense	1	Likely Pathogenic	0.000000
75.	c.2875_2876delAC	p.Thr959GlyfsX91	frameshift	1	Pathogenic	0.000000
76.	c.3690_3691delCA	p.Phe1230LeufsX11	frameshift	1	Pathogenic	0.000000
77.	c.2437A>T	p.K813X	nonsense	1	Pathogenic	0.000000
78.	c.1090+1G>T		essential splice site	1	Pathogenic	0.000000
79.	c.3253G>T	p.E1085X	nonsense	1	Pathogenic	0.000000
80.	c.3476_3477delTT		frameshift	1	Pathogenic	0.000000
81.	c.290C>T	p.A97V	missense	1	VUS favour pathogenic	0.000000
82.	c.3797G>A	p.C1266Y	missense	1	Likely Pathogenic	0.000000
83.	c.2780_2781delCA		frameshift	1	Pathogenic	0.000000
84.	c.993_994insT	p.E332X	nonsense	1	Pathogenic	0.000000
85.	c.2528_2536delAGATGCGCG	p.Glu843_Arg845del	inframe	1	Pathogenic	0.000000
86.	c.1351+1G>A		essential splice site	1	Pathogenic	0.000000
87.	c.436A>C	p.T146P	missense	1	VUS	0.000000
88.	c.481C>A	p.P161T	missense	1	VUS favour pathogenic	0.000041
89.	c.506-1G>T		essential splice site	1	Pathogenic	0.000000
90.	c.2234A>G	p.D745G	missense	1	VUS	0.000000
91.	c.326C>T	p.A109V	missense	1	VUS	0.000000
92.	c.1021G>A	p.G341S	missense	1	VUS favour pathogenic	0.000025
93.	c.2040_2041insT	p.Val681CysfsX12	frameshift	1	Pathogenic	0.000000
94.	c.3580G>A	p.A1194T	missense	1	VUS	0.000008
95.	c.1188G>T	p.W396C	missense	1	VUS	0.000000
96.	c.3335G>A	p.W1112X	nonsense	1	Pathogenic	0.000000
97.	c.2459G>A	p.R820Q	missense	1	Likely Pathogenic	0.000016
98.	c.931T>A	p.S311T	missense	1	VUS	0.000000
99.	c.1540A>G	p.I514V	missense	1	VUS	0.000008
100.	c.3676C>T	p.R1226C	missense	1	VUS	0.000058
101.	c.1358C>T	p.P453L	missense	1	VUS	0.000008
102.	c.3049G>A	p.E1017K	missense	1	VUS favour benign	0.000085
103.	c.2938C>T	p.R980C	missense	1	VUS	0.000062
104.	c.2170C>T	p.R724W	missense	1	VUS	0.000019
105.	c.1294G>A	p.A432T	missense	1	VUS	0.000037
106.	c.3G>C	p.Met1?	missense	1	Likely Pathogenic	0.000000
107.	c.2557G>A	p.G853S	missense	1	VUS	0.000008
108.	c.3811C>T	p.R1271X	nonsense	1	Pathogenic	0.000025
109.	c.3040delC	p.Leu1014TrpfsX6	frameshift	1	Pathogenic	0.000000
110.	c.655-1G>A		essential splice site	1	Pathogenic	0.000000
111.	c.2737+2T>A		essential splice site	1	Pathogenic	0.000000
112.	c.2993A>G	p.Q998R	missense	1	VUS favour pathogenic	0.000000
113.	c.3605G>A	p.C1202Y	missense	1	Likely Pathogenic	0.000000
114.	c.613C>T	p.Q205X	nonsense	1	Pathogenic	0.000000
115.	c.3776delA		frameshift	1	Pathogenic	0.000000
116.	c.1213A>G	p.M405V	missense	1	Pathogenic	0.000000
117.	c.3332_3335dupAGTG	p.W1112X	nonsense	1	Pathogenic	0.000000
118.	c.1841A>G	p.Y614C	missense	1	VUS favour pathogenic	0.000000
119.	c.2671C>T	p.R891W	missense	1	Likely Pathogenic	0.000031
120.	c.2953A>T	p.K985X	nonsense	1	Pathogenic	0.000000
121.	c.2641G>A	p.V881I	missense	1	VUS	0.000018
122.	c.2939G>A	p.R980H	missense	1	VUS	0.000000
123.	c.1535T>A	p.L512Q	missense	1	VUS favour pathogenic	0.000000
124.	c.3815-1G>A		essential splice site	1	Pathogenic	0.000000
125.	c.1892delT		frameshift	1	Pathogenic	0.000000
126.	c.2449C>T	p.R817W	missense	1	VUS	0.000000
127.	c.3753T>G	p.Y1251X	nonsense	1	Pathogenic	0.000000
128.	c.3742G>A	p.G1248R	missense	1	VUS	0.000033
129.	c.518C>A	p.T173N	missense	1	VUS	0.000000
130.	c.1950C>G	p.D650E	missense	1	VUS	0.000000
131.	c.2654C>T	p.T885M	missense	1	VUS	0.000022
132.	c.2308+1G>A		essential splice site	1	Pathogenic	0.000000
133.	c.103C>T	p.R35W	missense	1	VUS	0.000056
134.	c.2737+1G>C		essential splice site	1	Pathogenic	0.000000
135.	c.3277G>T	p.G1093C	missense	1	VUS	0.000020
136.	c.2048G>A	p.W683X	nonsense	1	Pathogenic	0.000000
137.	c.3286G>T	p.E1096X	nonsense	1	Pathogenic	0.000000
138.	c.2308+1G>T		essential splice site	1	Pathogenic	0.000000
139.	c.3791G>A	p.C1264Y	missense	1	VUS	0.000008
140.	c.1678delG	p.Asp560ThrfsX19	frameshift	1	Pathogenic	0.000000
141.	c.2556_2557delinsTCT	p.Gly853fs	frameshift	1	Pathogenic	0.000000
142.	c.2149-1G>A		essential splice site	1	Pathogenic	0.000000
143.	c.821+1G>C		essential splice site	1	Pathogenic	0.000000
144.	c.3288delG		frameshift	1	Pathogenic	0.000000
145.	c.1156G>T	p.E386X	nonsense	1	Pathogenic	0.000000
146.	c.333_334insT	p.E112X	nonsense	1	Pathogenic	0.000000
147.	c.2906-2A>G		essential splice site	1	Pathogenic	0.000000
148.	c.533delT	p.Val178GlyfsX7	frameshift	1	Pathogenic	0.000000
149.	c.2524_2525insT	p.Tyr842LeufsX42	frameshift	1	Pathogenic	0.000000
150.	c.2610_2611insC	p.Ser871GlnfsX13	frameshift	1	Pathogenic	0.000000
151.	c.1628delA		frameshift	1	Pathogenic	0.000000
152.	c.3065G>A	p.R1022H	missense	1	VUS favour pathogenic	0.000000
153.	c.1090+1G>A		essential splice site	1	Pathogenic	0.000000
154.	c.833delG	p.Gly278GlufsX22	frameshift	1	Pathogenic	0.000000
155.	c.853G>A	p.D285N	missense	1	VUS	0.000000
156.	c.3694A>T	p.K1232X	nonsense	1	Pathogenic	0.000000
157.	c.3281A>T	p.N1094I	missense	1	VUS	0.000000
158.	c.1778C>T	p.S593F	missense	1	VUS favour pathogenic	0.000034
159.	c.1418T>C	p.F473S	missense	1	VUS	0.000000
160.	c.1672G>A	p.A558T	missense	1	VUS	0.000008
161.	c.2312T>C	p.V771A	missense	1	VUS	0.000000
162.	c.3373G>A	p.V1125M	missense	1	VUS favour pathogenic	0.000022
163.	c.2518G>A	p.V840M	missense	1	VUS	0.000016
164.	c.3413G>C	p.R1138P	missense	1	VUS	0.000000
165.	c.3415G>A	p.V1139I	missense	1	VUS	0.000087
166.	c.2210C>T	p.T737M	missense	1	VUS	0.000050
167.	c.373G>T	p.A125S	missense	1	VUS	0.000000
168.	c.2534_2538delGCGTC		frameshift	1	Pathogenic	0.000000
169.	c.3083C>G	p.T1028S	missense	1	VUS	0.000000
170.	c.1999_2000delinsG	p.Leu667AspfsX15	frameshift	1	Pathogenic	0.000000
171.	c.1693A>T	p.K565X	nonsense	1	Pathogenic	0.000000
172.	c.3065G>C	p.R1022P	missense	1	VUS favour pathogenic	0.000025
173.	c.1000G>T	p.E334X	nonsense	1	Pathogenic	0.000000
174.	c.844C>T	p.R282W	missense	1	VUS favour pathogenic	0.000000
175.	c.2723A>G	p.Y908C	missense	1	VUS	0.000062
176.	c.1699_1700delGA	p.Glu567GlyfsX4	frameshift	1	Pathogenic	0.000000
177.	c.1038_1042dupCGGCA		frameshift	1	Pathogenic	0.000008
178.	c.2394_2395insT	p.Gly799TrpfsX34	frameshift	1	Pathogenic	0.000000
179.	c.3166_3167insG	p.Ala1056GlyfsX9	frameshift	1	Pathogenic	0.000000
180.	c.1591G>C	p.G531R	missense	1	VUS favour pathogenic	0.000017
181.	c.1575T>G	p.Y525X	nonsense	1	Pathogenic	0.000000
182.	c.2747G>A	p.W916X	nonsense	1	Pathogenic	0.000000
183.	c.3408C>A	p.Y1136X	nonsense	1	Pathogenic	0.000000
184.	c.2533C>T	p.R845C	missense	1	VUS favour pathogenic	0.000000
185.	c.3735delC		frameshift	1	Likely Pathogenic	0.000000
186.	c.2965G>T	p.E989X	nonsense	1	Pathogenic	0.000000
187.	c.2490_2491insT	p.His831SerfsTer2	frameshift	1	Pathogenic	0.000024
188.	c.821+2T>C		essential splice site	1	Pathogenic	0.000000
189.	c.2163delC	p.Glu722ArgfsX32	frameshift	1	Pathogenic	0.000000
190.	c.1224-2A>G		essential splice site	1	Pathogenic	0.000000
191.	c.3476_3479dupTTAT	p.Pro1161TyrfsX9	frameshift	1	Pathogenic	0.000000
192.	c.2525A>G	p.Y842C	missense	1	VUS	0.000000
193.	c.459delC		frameshift	1	Pathogenic	0.000000
194.	c.2013_2016delinsGG	p.Pro672AspfsX20	frameshift	1	Pathogenic	0.000000
195.	c.3763G>A	p.A1255T	missense	1	VUS favour pathogenic	0.000075
196.	c.431_432delGT	p.Gly144AlafsX8	frameshift	1	Pathogenic	0.000000
197.	c.932C>T	p.S311L	missense	1	VUS	0.000000
198.	c.566T>A	p.V189D	missense	1	VUS	0.000000
199.	c.1397T>A	p.M466K	missense	1	VUS	0.000008
200.	c.2197C>T	p.R733C	missense	1	VUS	0.000085
201.	c.2436G>T	p.K812N	missense	1	VUS	0.000000
202.	c.2269G>A	p.V757M	missense	1	VUS	0.000066
203.	c.1960C>T	p.R654C	missense	1	VUS favour benign	0.000008
204.	c.2828G>A	p.R943Q	missense	1	VUS	0.000025
205.	c.3825A>G	p.X1275TrpextX77	nonsense	1	Likely Pathogenic	0.000000
206.	c.1168delC		frameshift	1	Pathogenic	0.000000
207.	c.451G>A	p.D151N	missense	1	VUS	0.000041
208.	c.1624+2T>C		essential splice site	1	Pathogenic	0.000000
209.	c.104G>A	p.R35Q	missense	1	VUS	0.000079
210.	c.177_187del	p.Glu60AlafsX49	frameshift	1	Pathogenic	0.000000
211.	c.1458-1G>A		essential splice site	1	Pathogenic	0.000000
212.	c.2541C>A	p.Y847X	nonsense	1	Pathogenic	0.000000
213.	c.3331-1G>A		essential splice site	1	Pathogenic	0.000000
214.	c.932C>A	p.S311X	nonsense	1	Pathogenic	0.000000
215.	c.1586C>G	p.T529S	missense	1	VUS favour pathogenic	0.000000
216.	c.1343T>C	p.F448S	missense	1	Likely Pathogenic	0.000000
217.	c.1924C>T	p.Q642X	nonsense	1	Pathogenic	0.000000
218.	c.551_552insT	p.Lys185GlufsX56	frameshift	1	Pathogenic	0.000000
219.	c.966G>A	p.W322X	nonsense	1	Pathogenic	0.000000
220.	c.1505G>T	p.R502L	missense	1	VUS favour pathogenic	0.000000
221.	c.3548T>G	p.F1183C	missense	1	Likely Pathogenic	0.000000
222.	c.3181C>T	p.Q1061X	nonsense	1	Pathogenic	0.000016
223.	c.2517_2538del	p.Val840ThrfsX32	frameshift	1	Pathogenic	0.000000
224.	c.223G>A	p.D75N	missense	1	VUS favour pathogenic	0.000091
225.	c.713G>A	p.R238H	missense	1	VUS	0.000074
226.	c.2560A>G	p.M854V	missense	1	VUS	0.000000
227.	c.3098G>A	p.R1033Q	missense	1	VUS	0.000000
228.	c.1800delA		frameshift	1	Pathogenic	0.000000
229.	c.3746G>T	p.G1249V	missense	1	VUS	0.000000
230.	c.2833_2834delCG		frameshift	1	Pathogenic	0.000000
231.	c.2905+1G>C		essential splice site	1	Pathogenic	0.000000
232.	c.3068_3069insA	p.Asn1023LysfsX28	frameshift	1	Pathogenic	0.000000
233.	c.2113_2114insA	p.Thr705AsnfsX3	frameshift	1	Pathogenic	0.000000
234.	c.1351+2T>C		essential splice site	1	Pathogenic	0.000000
235.	c.1273C>T	p.Q425X	nonsense	1	Pathogenic	0.000000
236.	c.3600_3609delCTGCTGTGCT		frameshift	0	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.