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