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