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