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.3226_3227insT		frameshift	6	Pathogenic	0.000000
16.	c.1505G>A	p.R502Q	missense	6	Pathogenic	0.000000
17.	c.2864_2865delCT		frameshift	6	Pathogenic	0.000000
18.	c.2308G>A	p.D770N	missense	6	Likely Pathogenic	0.000008
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.2905+1G>A		essential splice site	4	Pathogenic	0.000000
23.	c.3742_3759dup	p.Gly1248_Cys1253dup	inframe	4	Likely Pathogenic	0.000000
24.	c.1483C>G	p.R495G	missense	4	Likely Pathogenic	0.000000
25.	c.2454G>A	p.W818X	nonsense	4	Pathogenic	0.000000
26.	c.3064C>T	p.R1022C	missense	4	VUS favour pathogenic	0.000008
27.	c.2573G>A	p.S858N	missense	4	VUS favour pathogenic	0.000000
28.	c.2182G>T	p.E728X	nonsense	4	Pathogenic	0.000000
29.	c.26-2A>G		essential splice site	4	Pathogenic	0.000051
30.	c.2096delC		frameshift	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.3233G>A	p.W1078X	nonsense	3	Pathogenic	0.000022
39.	c.2920C>T	p.Q974X	nonsense	3	Pathogenic	0.000000
40.	c.355G>A	p.E119K	missense	3	VUS	0.000000
41.	c.3491-2A>T		essential splice site	3	Pathogenic	0.000000
42.	c.3190+1G>A		essential splice site	3	Pathogenic	0.000000
43.	c.2873C>T	p.T958I	missense	3	VUS favour benign	0.000065
44.	c.1357_1358delCC		frameshift	2	Pathogenic	0.000000
45.	c.1863delC	p.Phe621LeufsX42	frameshift	2	Pathogenic	0.000000
46.	c.3627+1G>A		essential splice site	2	Pathogenic	0.000000
47.	c.3192_3193insC	p.Lys1065GlnfsX12	frameshift	2	Pathogenic	0.000000
48.	c.1790G>A	p.R597Q	missense	2	VUS favour pathogenic	0.000000
49.	c.1483C>T	p.R495W	missense	2	VUS favour pathogenic	0.000000
50.	c.3624_3625insC	p.Lys1209GlnfsX33	frameshift	2	Pathogenic	0.000000
51.	c.2943_2947delGACCA		frameshift	2	Pathogenic	0.000000
52.	c.999C>G	p.Y333X	nonsense	2	Pathogenic	0.000000
53.	c.1766G>A	p.R589H	missense	2	VUS	0.000000
54.	c.927-2A>G		essential splice site	2	Pathogenic	0.000000
55.	c.2558delG		frameshift	2	Pathogenic	0.000000
56.	c.1895delT	p.Met632ArgfsX31	frameshift	2	Pathogenic	0.000000
57.	c.2882C>T	p.P961L	missense	2	VUS	0.000048
58.	c.1037G>A	p.R346H	missense	2	VUS	0.000000
59.	c.772+1G>A		essential splice site	2	Pathogenic	0.000000
60.	c.2604_2605delinsA	p.S871fs	frameshift	2	Pathogenic	0.000000
61.	c.1210C>T	p.Q404X	nonsense	2	Pathogenic	0.000000
62.	c.532G>A	p.V178M	missense	2	VUS favour pathogenic	0.000020
63.	c.436_437insA	p.Thr146AsnfsX7	frameshift	2	Pathogenic	0.000000
64.	c.1869C>A	p.C623X	nonsense	2	Pathogenic	0.000000
65.	c.3624delC		frameshift	2	Pathogenic	0.000000
66.	c.3190+2T>G		essential splice site	2	Pathogenic	0.000016
67.	c.1934C>T	p.P645L	missense	2	VUS	0.000000
68.	c.814C>T	p.R272C	missense	2	VUS	0.000083
69.	c.2320G>A	p.A774T	missense	2	VUS	0.000000
70.	c.1513_1515delAAG		inframe	2	VUS favour pathogenic	0.000000
71.	c.636C>G	p.S212R	missense	2	VUS favour pathogenic	0.000000
72.	c.1897+1G>A		essential splice site	2	Pathogenic	0.000000
73.	c.1828G>C	p.D610H	missense	2	VUS favour benign	0.000058
74.	c.3676C>T	p.R1226C	missense	1	VUS	0.000058
75.	c.1358C>T	p.P453L	missense	1	VUS	0.000008
76.	c.3049G>A	p.E1017K	missense	1	VUS favour benign	0.000085
77.	c.2938C>T	p.R980C	missense	1	VUS	0.000062
78.	c.2170C>T	p.R724W	missense	1	VUS	0.000019
79.	c.3G>C	p.Met1?	missense	1	Likely Pathogenic	0.000000
80.	c.2557G>A	p.G853S	missense	1	VUS	0.000008
81.	c.1294G>A	p.A432T	missense	1	VUS	0.000037
82.	c.3040delC	p.Leu1014TrpfsX6	frameshift	1	Pathogenic	0.000000
83.	c.655-1G>A		essential splice site	1	Pathogenic	0.000000
84.	c.2737+2T>A		essential splice site	1	Pathogenic	0.000000
85.	c.2993A>G	p.Q998R	missense	1	VUS favour pathogenic	0.000000
86.	c.3605G>A	p.C1202Y	missense	1	Likely Pathogenic	0.000000
87.	c.3811C>T	p.R1271X	nonsense	1	Pathogenic	0.000025
88.	c.3776delA		frameshift	1	Pathogenic	0.000000
89.	c.1213A>G	p.M405V	missense	1	Pathogenic	0.000000
90.	c.3332_3335dupAGTG	p.W1112X	nonsense	1	Pathogenic	0.000000
91.	c.1841A>G	p.Y614C	missense	1	VUS favour pathogenic	0.000000
92.	c.2671C>T	p.R891W	missense	1	Likely Pathogenic	0.000031
93.	c.2953A>T	p.K985X	nonsense	1	Pathogenic	0.000000
94.	c.613C>T	p.Q205X	nonsense	1	Pathogenic	0.000000
95.	c.2641G>A	p.V881I	missense	1	VUS	0.000018
96.	c.2939G>A	p.R980H	missense	1	VUS	0.000000
97.	c.1535T>A	p.L512Q	missense	1	VUS favour pathogenic	0.000000
98.	c.3815-1G>A		essential splice site	1	Pathogenic	0.000000
99.	c.1892delT		frameshift	1	Pathogenic	0.000000
100.	c.2449C>T	p.R817W	missense	1	VUS	0.000000
101.	c.3753T>G	p.Y1251X	nonsense	1	Pathogenic	0.000000
102.	c.1950C>G	p.D650E	missense	1	VUS	0.000000
103.	c.3742G>A	p.G1248R	missense	1	VUS	0.000033
104.	c.518C>A	p.T173N	missense	1	VUS	0.000000
105.	c.103C>T	p.R35W	missense	1	VUS	0.000056
106.	c.2833_2834delCG		frameshift	1	Pathogenic	0.000000
107.	c.2654C>T	p.T885M	missense	1	VUS	0.000022
108.	c.2737+1G>C		essential splice site	1	Pathogenic	0.000000
109.	c.3277G>T	p.G1093C	missense	1	VUS	0.000020
110.	c.2048G>A	p.W683X	nonsense	1	Pathogenic	0.000000
111.	c.3286G>T	p.E1096X	nonsense	1	Pathogenic	0.000000
112.	c.3791G>A	p.C1264Y	missense	1	VUS	0.000008
113.	c.2556_2557delinsTCT	p.Gly853fs	frameshift	1	Pathogenic	0.000000
114.	c.2149-1G>A		essential splice site	1	Pathogenic	0.000000
115.	c.821+1G>C		essential splice site	1	Pathogenic	0.000000
116.	c.3288delG		frameshift	1	Pathogenic	0.000000
117.	c.1678delG	p.Asp560ThrfsX19	frameshift	1	Pathogenic	0.000000
118.	c.2906-2A>G		essential splice site	1	Pathogenic	0.000000
119.	c.533delT	p.Val178GlyfsX7	frameshift	1	Pathogenic	0.000000
120.	c.2524_2525insT	p.Tyr842LeufsX42	frameshift	1	Pathogenic	0.000000
121.	c.1156G>T	p.E386X	nonsense	1	Pathogenic	0.000000
122.	c.333_334insT	p.E112X	nonsense	1	Pathogenic	0.000000
123.	c.1628delA		frameshift	1	Pathogenic	0.000000
124.	c.3065G>A	p.R1022H	missense	1	VUS favour pathogenic	0.000000
125.	c.1090+1G>A		essential splice site	1	Pathogenic	0.000000
126.	c.833delG	p.Gly278GlufsX22	frameshift	1	Pathogenic	0.000000
127.	c.2610_2611insC	p.Ser871GlnfsX13	frameshift	1	Pathogenic	0.000000
128.	c.853G>A	p.D285N	missense	1	VUS	0.000000
129.	c.3694A>T	p.K1232X	nonsense	1	Pathogenic	0.000000
130.	c.2459G>A	p.R820Q	missense	1	Likely Pathogenic	0.000016
131.	c.3281A>T	p.N1094I	missense	1	VUS	0.000000
132.	c.1778C>T	p.S593F	missense	1	VUS favour pathogenic	0.000034
133.	c.1418T>C	p.F473S	missense	1	VUS	0.000000
134.	c.2518G>A	p.V840M	missense	1	VUS	0.000016
135.	c.3413G>C	p.R1138P	missense	1	VUS	0.000000
136.	c.1672G>A	p.A558T	missense	1	VUS	0.000008
137.	c.2312T>C	p.V771A	missense	1	VUS	0.000000
138.	c.373G>T	p.A125S	missense	1	VUS	0.000000
139.	c.3083C>G	p.T1028S	missense	1	VUS	0.000000
140.	c.3415G>A	p.V1139I	missense	1	VUS	0.000087
141.	c.2210C>T	p.T737M	missense	1	VUS	0.000050
142.	c.1693A>T	p.K565X	nonsense	1	Pathogenic	0.000000
143.	c.3065G>C	p.R1022P	missense	1	VUS favour pathogenic	0.000025
144.	c.1000G>T	p.E334X	nonsense	1	Pathogenic	0.000000
145.	c.844C>T	p.R282W	missense	1	VUS favour pathogenic	0.000000
146.	c.2723A>G	p.Y908C	missense	1	VUS	0.000062
147.	c.1699_1700delGA	p.Glu567GlyfsX4	frameshift	1	Pathogenic	0.000000
148.	c.1999_2000delinsG	p.Leu667AspfsX15	frameshift	1	Pathogenic	0.000000
149.	c.2394_2395insT	p.Gly799TrpfsX34	frameshift	1	Pathogenic	0.000000
150.	c.3166_3167insG	p.Ala1056GlyfsX9	frameshift	1	Pathogenic	0.000000
151.	c.1591G>C	p.G531R	missense	1	VUS favour pathogenic	0.000017
152.	c.1575T>G	p.Y525X	nonsense	1	Pathogenic	0.000000
153.	c.2747G>A	p.W916X	nonsense	1	Pathogenic	0.000000
154.	c.1038_1042dupCGGCA		frameshift	1	Pathogenic	0.000008
155.	c.2490_2491insT	p.His831SerfsTer2	frameshift	1	Pathogenic	0.000024
156.	c.821+2T>C		essential splice site	1	Pathogenic	0.000000
157.	c.2163delC	p.Glu722ArgfsX32	frameshift	1	Pathogenic	0.000000
158.	c.1224-2A>G		essential splice site	1	Pathogenic	0.000000
159.	c.3476_3479dupTTAT	p.Pro1161TyrfsX9	frameshift	1	Pathogenic	0.000000
160.	c.3408C>A	p.Y1136X	nonsense	1	Pathogenic	0.000000
161.	c.2533C>T	p.R845C	missense	1	VUS favour pathogenic	0.000000
162.	c.3735delC		frameshift	1	Likely Pathogenic	0.000000
163.	c.2965G>T	p.E989X	nonsense	1	Pathogenic	0.000000
164.	c.2013_2016delinsGG	p.Pro672AspfsX20	frameshift	1	Pathogenic	0.000000
165.	c.3763G>A	p.A1255T	missense	1	VUS favour pathogenic	0.000075
166.	c.431_432delGT	p.Gly144AlafsX8	frameshift	1	Pathogenic	0.000000
167.	c.2525A>G	p.Y842C	missense	1	VUS	0.000000
168.	c.459delC		frameshift	1	Pathogenic	0.000000
169.	c.932C>T	p.S311L	missense	1	VUS	0.000000
170.	c.566T>A	p.V189D	missense	1	VUS	0.000000
171.	c.1397T>A	p.M466K	missense	1	VUS	0.000008
172.	c.2197C>T	p.R733C	missense	1	VUS	0.000085
173.	c.2436G>T	p.K812N	missense	1	VUS	0.000000
174.	c.2269G>A	p.V757M	missense	1	VUS	0.000066
175.	c.1960C>T	p.R654C	missense	1	VUS favour benign	0.000008
176.	c.2308+1G>A		essential splice site	1	Pathogenic	0.000000
177.	c.2828G>A	p.R943Q	missense	1	VUS	0.000025
178.	c.1624+2T>C		essential splice site	1	Pathogenic	0.000000
179.	c.104G>A	p.R35Q	missense	1	VUS	0.000079
180.	c.3825A>G	p.X1275TrpextX77	nonsense	1	Likely Pathogenic	0.000000
181.	c.1168delC		frameshift	1	Pathogenic	0.000000
182.	c.451G>A	p.D151N	missense	1	VUS	0.000041
183.	c.177_187del	p.Glu60AlafsX49	frameshift	1	Pathogenic	0.000000
184.	c.2308+1G>T		essential splice site	1	Pathogenic	0.000000
185.	c.1458-1G>A		essential splice site	1	Pathogenic	0.000000
186.	c.3331-1G>A		essential splice site	1	Pathogenic	0.000000
187.	c.932C>A	p.S311X	nonsense	1	Pathogenic	0.000000
188.	c.1586C>G	p.T529S	missense	1	VUS favour pathogenic	0.000000
189.	c.1343T>C	p.F448S	missense	1	Likely Pathogenic	0.000000
190.	c.1924C>T	p.Q642X	nonsense	1	Pathogenic	0.000000
191.	c.551_552insT	p.Lys185GlufsX56	frameshift	1	Pathogenic	0.000000
192.	c.2541C>A	p.Y847X	nonsense	1	Pathogenic	0.000000
193.	c.3548T>G	p.F1183C	missense	1	Likely Pathogenic	0.000000
194.	c.966G>A	p.W322X	nonsense	1	Pathogenic	0.000000
195.	c.1505G>T	p.R502L	missense	1	VUS favour pathogenic	0.000000
196.	c.3181C>T	p.Q1061X	nonsense	1	Pathogenic	0.000016
197.	c.2517_2538del	p.Val840ThrfsX32	frameshift	1	Pathogenic	0.000000
198.	c.3373G>A	p.V1125M	missense	1	VUS favour pathogenic	0.000022
199.	c.223G>A	p.D75N	missense	1	VUS favour pathogenic	0.000091
200.	c.713G>A	p.R238H	missense	1	VUS	0.000074
201.	c.2534_2538delGCGTC		frameshift	1	Pathogenic	0.000000
202.	c.2560A>G	p.M854V	missense	1	VUS	0.000000
203.	c.1800delA		frameshift	1	Pathogenic	0.000000
204.	c.3746G>T	p.G1249V	missense	1	VUS	0.000000
205.	c.2905+1G>C		essential splice site	1	Pathogenic	0.000000
206.	c.3098G>A	p.R1033Q	missense	1	VUS	0.000000
207.	c.2113_2114insA	p.Thr705AsnfsX3	frameshift	1	Pathogenic	0.000000
208.	c.1351+2T>C		essential splice site	1	Pathogenic	0.000000
209.	c.1273C>T	p.Q425X	nonsense	1	Pathogenic	0.000000
210.	c.3068_3069insA	p.Asn1023LysfsX28	frameshift	1	Pathogenic	0.000000
211.	c.2875_2876delAC	p.Thr959GlyfsX91	frameshift	1	Pathogenic	0.000000
212.	c.3690_3691delCA	p.Phe1230LeufsX11	frameshift	1	Pathogenic	0.000000
213.	c.2437A>T	p.K813X	nonsense	1	Pathogenic	0.000000
214.	c.1090+1G>T		essential splice site	1	Pathogenic	0.000000
215.	c.3253G>T	p.E1085X	nonsense	1	Pathogenic	0.000000
216.	c.1456T>G	p.W486G	missense	1	Likely Pathogenic	0.000000
217.	c.3476_3477delTT		frameshift	1	Pathogenic	0.000000
218.	c.290C>T	p.A97V	missense	1	VUS favour pathogenic	0.000000
219.	c.3797G>A	p.C1266Y	missense	1	Likely Pathogenic	0.000000
220.	c.2780_2781delCA		frameshift	1	Pathogenic	0.000000
221.	c.993_994insT	p.E332X	nonsense	1	Pathogenic	0.000000
222.	c.2528_2536delAGATGCGCG	p.Glu843_Arg845del	inframe	1	Pathogenic	0.000000
223.	c.1351+1G>A		essential splice site	1	Pathogenic	0.000000
224.	c.2234A>G	p.D745G	missense	1	VUS	0.000000
225.	c.326C>T	p.A109V	missense	1	VUS	0.000000
226.	c.1021G>A	p.G341S	missense	1	VUS favour pathogenic	0.000025
227.	c.2040_2041insT	p.Val681CysfsX12	frameshift	1	Pathogenic	0.000000
228.	c.3580G>A	p.A1194T	missense	1	VUS	0.000008
229.	c.1188G>T	p.W396C	missense	1	VUS	0.000000
230.	c.3335G>A	p.W1112X	nonsense	1	Pathogenic	0.000000
231.	c.436A>C	p.T146P	missense	1	VUS	0.000000
232.	c.481C>A	p.P161T	missense	1	VUS favour pathogenic	0.000041
233.	c.506-1G>T		essential splice site	1	Pathogenic	0.000000
234.	c.931T>A	p.S311T	missense	1	VUS	0.000000
235.	c.1540A>G	p.I514V	missense	1	VUS	0.000008
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.