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