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