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.913_914delTT		frameshift	5	Pathogenic	0.000000
20.	c.2374T>C	p.W792R	missense	5	Likely Pathogenic	0.000000
21.	c.3064C>T	p.R1022C	missense	4	VUS favour pathogenic	0.000008
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.2096delC		frameshift	4	Pathogenic	0.000000
25.	c.26-2A>G		essential splice site	4	Pathogenic	0.000051
26.	c.821+1G>A		essential splice site	4	Pathogenic	0.000043
27.	c.1483C>G	p.R495G	missense	4	Likely Pathogenic	0.000000
28.	c.2905+1G>A		essential splice site	4	Pathogenic	0.000000
29.	c.3742_3759dup	p.Gly1248_Cys1253dup	inframe	4	Likely Pathogenic	0.000000
30.	c.2454G>A	p.W818X	nonsense	4	Pathogenic	0.000000
31.	c.3767_3769delCCA	p.Thr1256del	inframe	3	Likely Pathogenic	0.000000
32.	c.2905C>T	p.Q969X	nonsense	3	Pathogenic	0.000000
33.	c.1828G>A	p.D610N	missense	3	VUS	0.000000
34.	c.710A>C	p.Y237S	missense	3	Likely Pathogenic	0.000000
35.	c.2450G>A	p.R817Q	missense	3	VUS favour pathogenic	0.000016
36.	c.3190+1G>A		essential splice site	3	Pathogenic	0.000000
37.	c.3233G>A	p.W1078X	nonsense	3	Pathogenic	0.000022
38.	c.2920C>T	p.Q974X	nonsense	3	Pathogenic	0.000000
39.	c.355G>A	p.E119K	missense	3	VUS	0.000000
40.	c.3491-2A>T		essential splice site	3	Pathogenic	0.000000
41.	c.2873C>T	p.T958I	missense	3	VUS favour benign	0.000065
42.	c.2311_2312insG	p.Val771GlyfsX62	frameshift	3	Pathogenic	0.000000
43.	c.1591G>A	p.G531R	missense	3	VUS favour pathogenic	0.000017
44.	c.3192_3193insC	p.Lys1065GlnfsX12	frameshift	2	Pathogenic	0.000000
45.	c.1790G>A	p.R597Q	missense	2	VUS favour pathogenic	0.000000
46.	c.1483C>T	p.R495W	missense	2	VUS favour pathogenic	0.000000
47.	c.3624_3625insC	p.Lys1209GlnfsX33	frameshift	2	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.1766G>A	p.R589H	missense	2	VUS	0.000000
51.	c.927-2A>G		essential splice site	2	Pathogenic	0.000000
52.	c.2558delG		frameshift	2	Pathogenic	0.000000
53.	c.1895delT	p.Met632ArgfsX31	frameshift	2	Pathogenic	0.000000
54.	c.2882C>T	p.P961L	missense	2	VUS	0.000048
55.	c.1037G>A	p.R346H	missense	2	VUS	0.000000
56.	c.772+1G>A		essential splice site	2	Pathogenic	0.000000
57.	c.2604_2605delinsA	p.S871fs	frameshift	2	Pathogenic	0.000000
58.	c.532G>A	p.V178M	missense	2	VUS favour pathogenic	0.000020
59.	c.1210C>T	p.Q404X	nonsense	2	Pathogenic	0.000000
60.	c.3190+2T>G		essential splice site	2	Pathogenic	0.000016
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.1934C>T	p.P645L	missense	2	VUS	0.000000
65.	c.814C>T	p.R272C	missense	2	VUS	0.000083
66.	c.2320G>A	p.A774T	missense	2	VUS	0.000000
67.	c.1513_1515delAAG		inframe	2	VUS favour pathogenic	0.000000
68.	c.636C>G	p.S212R	missense	2	VUS favour pathogenic	0.000000
69.	c.1897+1G>A		essential splice site	2	Pathogenic	0.000000
70.	c.1828G>C	p.D610H	missense	2	VUS favour benign	0.000058
71.	c.1357_1358delCC		frameshift	2	Pathogenic	0.000000
72.	c.3627+1G>A		essential splice site	2	Pathogenic	0.000000
73.	c.1863delC	p.Phe621LeufsX42	frameshift	2	Pathogenic	0.000000
74.	c.3753T>G	p.Y1251X	nonsense	1	Pathogenic	0.000000
75.	c.2641G>A	p.V881I	missense	1	VUS	0.000018
76.	c.2939G>A	p.R980H	missense	1	VUS	0.000000
77.	c.1535T>A	p.L512Q	missense	1	VUS favour pathogenic	0.000000
78.	c.3815-1G>A		essential splice site	1	Pathogenic	0.000000
79.	c.1892delT		frameshift	1	Pathogenic	0.000000
80.	c.2449C>T	p.R817W	missense	1	VUS	0.000000
81.	c.3742G>A	p.G1248R	missense	1	VUS	0.000033
82.	c.518C>A	p.T173N	missense	1	VUS	0.000000
83.	c.1950C>G	p.D650E	missense	1	VUS	0.000000
84.	c.2654C>T	p.T885M	missense	1	VUS	0.000022
85.	c.3373G>A	p.V1125M	missense	1	VUS favour pathogenic	0.000022
86.	c.103C>T	p.R35W	missense	1	VUS	0.000056
87.	c.2737+1G>C		essential splice site	1	Pathogenic	0.000000
88.	c.3277G>T	p.G1093C	missense	1	VUS	0.000020
89.	c.2048G>A	p.W683X	nonsense	1	Pathogenic	0.000000
90.	c.2534_2538delGCGTC		frameshift	1	Pathogenic	0.000000
91.	c.3286G>T	p.E1096X	nonsense	1	Pathogenic	0.000000
92.	c.3791G>A	p.C1264Y	missense	1	VUS	0.000008
93.	c.3288delG		frameshift	1	Pathogenic	0.000000
94.	c.1678delG	p.Asp560ThrfsX19	frameshift	1	Pathogenic	0.000000
95.	c.2556_2557delinsTCT	p.Gly853fs	frameshift	1	Pathogenic	0.000000
96.	c.2149-1G>A		essential splice site	1	Pathogenic	0.000000
97.	c.821+1G>C		essential splice site	1	Pathogenic	0.000000
98.	c.1156G>T	p.E386X	nonsense	1	Pathogenic	0.000000
99.	c.333_334insT	p.E112X	nonsense	1	Pathogenic	0.000000
100.	c.2906-2A>G		essential splice site	1	Pathogenic	0.000000
101.	c.533delT	p.Val178GlyfsX7	frameshift	1	Pathogenic	0.000000
102.	c.2524_2525insT	p.Tyr842LeufsX42	frameshift	1	Pathogenic	0.000000
103.	c.2610_2611insC	p.Ser871GlnfsX13	frameshift	1	Pathogenic	0.000000
104.	c.1628delA		frameshift	1	Pathogenic	0.000000
105.	c.3065G>A	p.R1022H	missense	1	VUS favour pathogenic	0.000000
106.	c.1090+1G>A		essential splice site	1	Pathogenic	0.000000
107.	c.833delG	p.Gly278GlufsX22	frameshift	1	Pathogenic	0.000000
108.	c.1418T>C	p.F473S	missense	1	VUS	0.000000
109.	c.853G>A	p.D285N	missense	1	VUS	0.000000
110.	c.3694A>T	p.K1232X	nonsense	1	Pathogenic	0.000000
111.	c.3281A>T	p.N1094I	missense	1	VUS	0.000000
112.	c.1778C>T	p.S593F	missense	1	VUS favour pathogenic	0.000034
113.	c.1672G>A	p.A558T	missense	1	VUS	0.000008
114.	c.2312T>C	p.V771A	missense	1	VUS	0.000000
115.	c.2518G>A	p.V840M	missense	1	VUS	0.000016
116.	c.3413G>C	p.R1138P	missense	1	VUS	0.000000
117.	c.3415G>A	p.V1139I	missense	1	VUS	0.000087
118.	c.2210C>T	p.T737M	missense	1	VUS	0.000050
119.	c.373G>T	p.A125S	missense	1	VUS	0.000000
120.	c.3083C>G	p.T1028S	missense	1	VUS	0.000000
121.	c.1999_2000delinsG	p.Leu667AspfsX15	frameshift	1	Pathogenic	0.000000
122.	c.1693A>T	p.K565X	nonsense	1	Pathogenic	0.000000
123.	c.3065G>C	p.R1022P	missense	1	VUS favour pathogenic	0.000025
124.	c.1000G>T	p.E334X	nonsense	1	Pathogenic	0.000000
125.	c.844C>T	p.R282W	missense	1	VUS favour pathogenic	0.000000
126.	c.2723A>G	p.Y908C	missense	1	VUS	0.000062
127.	c.1699_1700delGA	p.Glu567GlyfsX4	frameshift	1	Pathogenic	0.000000
128.	c.1575T>G	p.Y525X	nonsense	1	Pathogenic	0.000000
129.	c.2747G>A	p.W916X	nonsense	1	Pathogenic	0.000000
130.	c.1038_1042dupCGGCA		frameshift	1	Pathogenic	0.000008
131.	c.2394_2395insT	p.Gly799TrpfsX34	frameshift	1	Pathogenic	0.000000
132.	c.3166_3167insG	p.Ala1056GlyfsX9	frameshift	1	Pathogenic	0.000000
133.	c.1591G>C	p.G531R	missense	1	VUS favour pathogenic	0.000017
134.	c.3408C>A	p.Y1136X	nonsense	1	Pathogenic	0.000000
135.	c.2533C>T	p.R845C	missense	1	VUS favour pathogenic	0.000000
136.	c.3735delC		frameshift	1	Likely Pathogenic	0.000000
137.	c.2965G>T	p.E989X	nonsense	1	Pathogenic	0.000000
138.	c.2490_2491insT	p.His831SerfsTer2	frameshift	1	Pathogenic	0.000024
139.	c.821+2T>C		essential splice site	1	Pathogenic	0.000000
140.	c.2163delC	p.Glu722ArgfsX32	frameshift	1	Pathogenic	0.000000
141.	c.1224-2A>G		essential splice site	1	Pathogenic	0.000000
142.	c.3476_3479dupTTAT	p.Pro1161TyrfsX9	frameshift	1	Pathogenic	0.000000
143.	c.2525A>G	p.Y842C	missense	1	VUS	0.000000
144.	c.459delC		frameshift	1	Pathogenic	0.000000
145.	c.2013_2016delinsGG	p.Pro672AspfsX20	frameshift	1	Pathogenic	0.000000
146.	c.3763G>A	p.A1255T	missense	1	VUS favour pathogenic	0.000075
147.	c.431_432delGT	p.Gly144AlafsX8	frameshift	1	Pathogenic	0.000000
148.	c.1960C>T	p.R654C	missense	1	VUS favour benign	0.000008
149.	c.932C>T	p.S311L	missense	1	VUS	0.000000
150.	c.566T>A	p.V189D	missense	1	VUS	0.000000
151.	c.1397T>A	p.M466K	missense	1	VUS	0.000008
152.	c.2197C>T	p.R733C	missense	1	VUS	0.000085
153.	c.2436G>T	p.K812N	missense	1	VUS	0.000000
154.	c.2269G>A	p.V757M	missense	1	VUS	0.000066
155.	c.2308+1G>T		essential splice site	1	Pathogenic	0.000000
156.	c.2828G>A	p.R943Q	missense	1	VUS	0.000025
157.	c.3825A>G	p.X1275TrpextX77	nonsense	1	Likely Pathogenic	0.000000
158.	c.1168delC		frameshift	1	Pathogenic	0.000000
159.	c.451G>A	p.D151N	missense	1	VUS	0.000041
160.	c.1624+2T>C		essential splice site	1	Pathogenic	0.000000
161.	c.104G>A	p.R35Q	missense	1	VUS	0.000079
162.	c.2833_2834delCG		frameshift	1	Pathogenic	0.000000
163.	c.177_187del	p.Glu60AlafsX49	frameshift	1	Pathogenic	0.000000
164.	c.1458-1G>A		essential splice site	1	Pathogenic	0.000000
165.	c.551_552insT	p.Lys185GlufsX56	frameshift	1	Pathogenic	0.000000
166.	c.2541C>A	p.Y847X	nonsense	1	Pathogenic	0.000000
167.	c.3331-1G>A		essential splice site	1	Pathogenic	0.000000
168.	c.932C>A	p.S311X	nonsense	1	Pathogenic	0.000000
169.	c.1586C>G	p.T529S	missense	1	VUS favour pathogenic	0.000000
170.	c.1343T>C	p.F448S	missense	1	Likely Pathogenic	0.000000
171.	c.1924C>T	p.Q642X	nonsense	1	Pathogenic	0.000000
172.	c.966G>A	p.W322X	nonsense	1	Pathogenic	0.000000
173.	c.1505G>T	p.R502L	missense	1	VUS favour pathogenic	0.000000
174.	c.3548T>G	p.F1183C	missense	1	Likely Pathogenic	0.000000
175.	c.3181C>T	p.Q1061X	nonsense	1	Pathogenic	0.000016
176.	c.2517_2538del	p.Val840ThrfsX32	frameshift	1	Pathogenic	0.000000
177.	c.223G>A	p.D75N	missense	1	VUS favour pathogenic	0.000091
178.	c.2459G>A	p.R820Q	missense	1	Likely Pathogenic	0.000016
179.	c.713G>A	p.R238H	missense	1	VUS	0.000074
180.	c.2560A>G	p.M854V	missense	1	VUS	0.000000
181.	c.2905+1G>C		essential splice site	1	Pathogenic	0.000000
182.	c.3098G>A	p.R1033Q	missense	1	VUS	0.000000
183.	c.1800delA		frameshift	1	Pathogenic	0.000000
184.	c.3746G>T	p.G1249V	missense	1	VUS	0.000000
185.	c.3068_3069insA	p.Asn1023LysfsX28	frameshift	1	Pathogenic	0.000000
186.	c.2113_2114insA	p.Thr705AsnfsX3	frameshift	1	Pathogenic	0.000000
187.	c.1351+2T>C		essential splice site	1	Pathogenic	0.000000
188.	c.1273C>T	p.Q425X	nonsense	1	Pathogenic	0.000000
189.	c.1456T>G	p.W486G	missense	1	Likely Pathogenic	0.000000
190.	c.2875_2876delAC	p.Thr959GlyfsX91	frameshift	1	Pathogenic	0.000000
191.	c.3690_3691delCA	p.Phe1230LeufsX11	frameshift	1	Pathogenic	0.000000
192.	c.2437A>T	p.K813X	nonsense	1	Pathogenic	0.000000
193.	c.1090+1G>T		essential splice site	1	Pathogenic	0.000000
194.	c.3253G>T	p.E1085X	nonsense	1	Pathogenic	0.000000
195.	c.2528_2536delAGATGCGCG	p.Glu843_Arg845del	inframe	1	Pathogenic	0.000000
196.	c.1351+1G>A		essential splice site	1	Pathogenic	0.000000
197.	c.3476_3477delTT		frameshift	1	Pathogenic	0.000000
198.	c.290C>T	p.A97V	missense	1	VUS favour pathogenic	0.000000
199.	c.3797G>A	p.C1266Y	missense	1	Likely Pathogenic	0.000000
200.	c.2780_2781delCA		frameshift	1	Pathogenic	0.000000
201.	c.993_994insT	p.E332X	nonsense	1	Pathogenic	0.000000
202.	c.436A>C	p.T146P	missense	1	VUS	0.000000
203.	c.481C>A	p.P161T	missense	1	VUS favour pathogenic	0.000041
204.	c.506-1G>T		essential splice site	1	Pathogenic	0.000000
205.	c.2234A>G	p.D745G	missense	1	VUS	0.000000
206.	c.326C>T	p.A109V	missense	1	VUS	0.000000
207.	c.1021G>A	p.G341S	missense	1	VUS favour pathogenic	0.000025
208.	c.2040_2041insT	p.Val681CysfsX12	frameshift	1	Pathogenic	0.000000
209.	c.3580G>A	p.A1194T	missense	1	VUS	0.000008
210.	c.1188G>T	p.W396C	missense	1	VUS	0.000000
211.	c.3335G>A	p.W1112X	nonsense	1	Pathogenic	0.000000
212.	c.931T>A	p.S311T	missense	1	VUS	0.000000
213.	c.1540A>G	p.I514V	missense	1	VUS	0.000008
214.	c.2170C>T	p.R724W	missense	1	VUS	0.000019
215.	c.3676C>T	p.R1226C	missense	1	VUS	0.000058
216.	c.1358C>T	p.P453L	missense	1	VUS	0.000008
217.	c.3049G>A	p.E1017K	missense	1	VUS favour benign	0.000085
218.	c.2938C>T	p.R980C	missense	1	VUS	0.000062
219.	c.2308+1G>A		essential splice site	1	Pathogenic	0.000000
220.	c.1294G>A	p.A432T	missense	1	VUS	0.000037
221.	c.3G>C	p.Met1?	missense	1	Likely Pathogenic	0.000000
222.	c.2557G>A	p.G853S	missense	1	VUS	0.000008
223.	c.3811C>T	p.R1271X	nonsense	1	Pathogenic	0.000025
224.	c.3040delC	p.Leu1014TrpfsX6	frameshift	1	Pathogenic	0.000000
225.	c.655-1G>A		essential splice site	1	Pathogenic	0.000000
226.	c.2737+2T>A		essential splice site	1	Pathogenic	0.000000
227.	c.2993A>G	p.Q998R	missense	1	VUS favour pathogenic	0.000000
228.	c.3605G>A	p.C1202Y	missense	1	Likely Pathogenic	0.000000
229.	c.613C>T	p.Q205X	nonsense	1	Pathogenic	0.000000
230.	c.3776delA		frameshift	1	Pathogenic	0.000000
231.	c.1213A>G	p.M405V	missense	1	Pathogenic	0.000000
232.	c.3332_3335dupAGTG	p.W1112X	nonsense	1	Pathogenic	0.000000
233.	c.1841A>G	p.Y614C	missense	1	VUS favour pathogenic	0.000000
234.	c.2671C>T	p.R891W	missense	1	Likely Pathogenic	0.000031
235.	c.2953A>T	p.K985X	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.