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