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