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.2864_2865delCT		frameshift	6	Pathogenic	0.000000
16.	c.3226_3227insT		frameshift	6	Pathogenic	0.000000
17.	c.2308G>A	p.D770N	missense	6	Likely Pathogenic	0.000008
18.	c.1505G>A	p.R502Q	missense	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.3233G>A	p.W1078X	nonsense	3	Pathogenic	0.000022
32.	c.3767_3769delCCA	p.Thr1256del	inframe	3	Likely Pathogenic	0.000000
33.	c.2920C>T	p.Q974X	nonsense	3	Pathogenic	0.000000
34.	c.3491-2A>T		essential splice site	3	Pathogenic	0.000000
35.	c.2873C>T	p.T958I	missense	3	VUS favour benign	0.000065
36.	c.2311_2312insG	p.Val771GlyfsX62	frameshift	3	Pathogenic	0.000000
37.	c.1591G>A	p.G531R	missense	3	VUS favour pathogenic	0.000017
38.	c.2905C>T	p.Q969X	nonsense	3	Pathogenic	0.000000
39.	c.1828G>A	p.D610N	missense	3	VUS	0.000000
40.	c.355G>A	p.E119K	missense	3	VUS	0.000000
41.	c.710A>C	p.Y237S	missense	3	Likely Pathogenic	0.000000
42.	c.2450G>A	p.R817Q	missense	3	VUS favour pathogenic	0.000016
43.	c.3190+1G>A		essential splice site	3	Pathogenic	0.000000
44.	c.2558delG		frameshift	2	Pathogenic	0.000000
45.	c.1895delT	p.Met632ArgfsX31	frameshift	2	Pathogenic	0.000000
46.	c.2882C>T	p.P961L	missense	2	VUS	0.000048
47.	c.772+1G>A		essential splice site	2	Pathogenic	0.000000
48.	c.2604_2605delinsA	p.S871fs	frameshift	2	Pathogenic	0.000000
49.	c.532G>A	p.V178M	missense	2	VUS favour pathogenic	0.000020
50.	c.1210C>T	p.Q404X	nonsense	2	Pathogenic	0.000000
51.	c.3190+2T>G		essential splice site	2	Pathogenic	0.000016
52.	c.1869C>A	p.C623X	nonsense	2	Pathogenic	0.000000
53.	c.3624delC		frameshift	2	Pathogenic	0.000000
54.	c.814C>T	p.R272C	missense	2	VUS	0.000083
55.	c.2320G>A	p.A774T	missense	2	VUS	0.000000
56.	c.1513_1515delAAG		inframe	2	VUS favour pathogenic	0.000000
57.	c.1897+1G>A		essential splice site	2	Pathogenic	0.000000
58.	c.636C>G	p.S212R	missense	2	VUS favour pathogenic	0.000000
59.	c.1828G>C	p.D610H	missense	2	VUS favour benign	0.000058
60.	c.1357_1358delCC		frameshift	2	Pathogenic	0.000000
61.	c.1037G>A	p.R346H	missense	2	VUS	0.000000
62.	c.3627+1G>A		essential splice site	2	Pathogenic	0.000000
63.	c.1863delC	p.Phe621LeufsX42	frameshift	2	Pathogenic	0.000000
64.	c.436_437insA	p.Thr146AsnfsX7	frameshift	2	Pathogenic	0.000000
65.	c.1934C>T	p.P645L	missense	2	VUS	0.000000
66.	c.3192_3193insC	p.Lys1065GlnfsX12	frameshift	2	Pathogenic	0.000000
67.	c.1483C>T	p.R495W	missense	2	VUS favour pathogenic	0.000000
68.	c.1790G>A	p.R597Q	missense	2	VUS favour pathogenic	0.000000
69.	c.2943_2947delGACCA		frameshift	2	Pathogenic	0.000000
70.	c.999C>G	p.Y333X	nonsense	2	Pathogenic	0.000000
71.	c.3624_3625insC	p.Lys1209GlnfsX33	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.1188G>T	p.W396C	missense	1	VUS	0.000000
75.	c.1699_1700delGA	p.Glu567GlyfsX4	frameshift	1	Pathogenic	0.000000
76.	c.436A>C	p.T146P	missense	1	VUS	0.000000
77.	c.506-1G>T		essential splice site	1	Pathogenic	0.000000
78.	c.1999_2000delinsG	p.Leu667AspfsX15	frameshift	1	Pathogenic	0.000000
79.	c.1693A>T	p.K565X	nonsense	1	Pathogenic	0.000000
80.	c.326C>T	p.A109V	missense	1	VUS	0.000000
81.	c.3065G>C	p.R1022P	missense	1	VUS favour pathogenic	0.000025
82.	c.2040_2041insT	p.Val681CysfsX12	frameshift	1	Pathogenic	0.000000
83.	c.1000G>T	p.E334X	nonsense	1	Pathogenic	0.000000
84.	c.844C>T	p.R282W	missense	1	VUS favour pathogenic	0.000000
85.	c.2723A>G	p.Y908C	missense	1	VUS	0.000062
86.	c.1575T>G	p.Y525X	nonsense	1	Pathogenic	0.000000
87.	c.2747G>A	p.W916X	nonsense	1	Pathogenic	0.000000
88.	c.1038_1042dupCGGCA		frameshift	1	Pathogenic	0.000008
89.	c.2394_2395insT	p.Gly799TrpfsX34	frameshift	1	Pathogenic	0.000000
90.	c.931T>A	p.S311T	missense	1	VUS	0.000000
91.	c.3166_3167insG	p.Ala1056GlyfsX9	frameshift	1	Pathogenic	0.000000
92.	c.1591G>C	p.G531R	missense	1	VUS favour pathogenic	0.000017
93.	c.1224-2A>G		essential splice site	1	Pathogenic	0.000000
94.	c.3476_3479dupTTAT	p.Pro1161TyrfsX9	frameshift	1	Pathogenic	0.000000
95.	c.3408C>A	p.Y1136X	nonsense	1	Pathogenic	0.000000
96.	c.3735delC		frameshift	1	Likely Pathogenic	0.000000
97.	c.2965G>T	p.E989X	nonsense	1	Pathogenic	0.000000
98.	c.2490_2491insT	p.His831SerfsTer2	frameshift	1	Pathogenic	0.000024
99.	c.821+2T>C		essential splice site	1	Pathogenic	0.000000
100.	c.3763G>A	p.A1255T	missense	1	VUS favour pathogenic	0.000075
101.	c.459delC		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.1397T>A	p.M466K	missense	1	VUS	0.000008
106.	c.2197C>T	p.R733C	missense	1	VUS	0.000085
107.	c.1841A>G	p.Y614C	missense	1	VUS favour pathogenic	0.000000
108.	c.2308+1G>T		essential splice site	1	Pathogenic	0.000000
109.	c.2828G>A	p.R943Q	missense	1	VUS	0.000025
110.	c.1624+2T>C		essential splice site	1	Pathogenic	0.000000
111.	c.104G>A	p.R35Q	missense	1	VUS	0.000079
112.	c.2833_2834delCG		frameshift	1	Pathogenic	0.000000
113.	c.2449C>T	p.R817W	missense	1	VUS	0.000000
114.	c.3825A>G	p.X1275TrpextX77	nonsense	1	Likely Pathogenic	0.000000
115.	c.1168delC		frameshift	1	Pathogenic	0.000000
116.	c.451G>A	p.D151N	missense	1	VUS	0.000041
117.	c.2939G>A	p.R980H	missense	1	VUS	0.000000
118.	c.3815-1G>A		essential splice site	1	Pathogenic	0.000000
119.	c.518C>A	p.T173N	missense	1	VUS	0.000000
120.	c.177_187del	p.Glu60AlafsX49	frameshift	1	Pathogenic	0.000000
121.	c.1950C>G	p.D650E	missense	1	VUS	0.000000
122.	c.1458-1G>A		essential splice site	1	Pathogenic	0.000000
123.	c.1924C>T	p.Q642X	nonsense	1	Pathogenic	0.000000
124.	c.551_552insT	p.Lys185GlufsX56	frameshift	1	Pathogenic	0.000000
125.	c.2541C>A	p.Y847X	nonsense	1	Pathogenic	0.000000
126.	c.3331-1G>A		essential splice site	1	Pathogenic	0.000000
127.	c.932C>A	p.S311X	nonsense	1	Pathogenic	0.000000
128.	c.1343T>C	p.F448S	missense	1	Likely Pathogenic	0.000000
129.	c.1505G>T	p.R502L	missense	1	VUS favour pathogenic	0.000000
130.	c.223G>A	p.D75N	missense	1	VUS favour pathogenic	0.000091
131.	c.3181C>T	p.Q1061X	nonsense	1	Pathogenic	0.000016
132.	c.2560A>G	p.M854V	missense	1	VUS	0.000000
133.	c.2459G>A	p.R820Q	missense	1	Likely Pathogenic	0.000016
134.	c.713G>A	p.R238H	missense	1	VUS	0.000074
135.	c.833delG	p.Gly278GlufsX22	frameshift	1	Pathogenic	0.000000
136.	c.2905+1G>C		essential splice site	1	Pathogenic	0.000000
137.	c.3098G>A	p.R1033Q	missense	1	VUS	0.000000
138.	c.2610_2611insC	p.Ser871GlnfsX13	frameshift	1	Pathogenic	0.000000
139.	c.1800delA		frameshift	1	Pathogenic	0.000000
140.	c.3065G>A	p.R1022H	missense	1	VUS favour pathogenic	0.000000
141.	c.3746G>T	p.G1249V	missense	1	VUS	0.000000
142.	c.1351+2T>C		essential splice site	1	Pathogenic	0.000000
143.	c.1273C>T	p.Q425X	nonsense	1	Pathogenic	0.000000
144.	c.1418T>C	p.F473S	missense	1	VUS	0.000000
145.	c.3068_3069insA	p.Asn1023LysfsX28	frameshift	1	Pathogenic	0.000000
146.	c.853G>A	p.D285N	missense	1	VUS	0.000000
147.	c.3694A>T	p.K1232X	nonsense	1	Pathogenic	0.000000
148.	c.2113_2114insA	p.Thr705AsnfsX3	frameshift	1	Pathogenic	0.000000
149.	c.3281A>T	p.N1094I	missense	1	VUS	0.000000
150.	c.1090+1G>T		essential splice site	1	Pathogenic	0.000000
151.	c.3413G>C	p.R1138P	missense	1	VUS	0.000000
152.	c.3253G>T	p.E1085X	nonsense	1	Pathogenic	0.000000
153.	c.1456T>G	p.W486G	missense	1	Likely Pathogenic	0.000000
154.	c.2875_2876delAC	p.Thr959GlyfsX91	frameshift	1	Pathogenic	0.000000
155.	c.3690_3691delCA	p.Phe1230LeufsX11	frameshift	1	Pathogenic	0.000000
156.	c.2437A>T	p.K813X	nonsense	1	Pathogenic	0.000000
157.	c.1351+1G>A		essential splice site	1	Pathogenic	0.000000
158.	c.3476_3477delTT		frameshift	1	Pathogenic	0.000000
159.	c.3797G>A	p.C1266Y	missense	1	Likely Pathogenic	0.000000
160.	c.2780_2781delCA		frameshift	1	Pathogenic	0.000000
161.	c.993_994insT	p.E332X	nonsense	1	Pathogenic	0.000000
162.	c.3335G>A	p.W1112X	nonsense	1	Pathogenic	0.000000
163.	c.481C>A	p.P161T	missense	1	VUS favour pathogenic	0.000041
164.	c.2234A>G	p.D745G	missense	1	VUS	0.000000
165.	c.1021G>A	p.G341S	missense	1	VUS favour pathogenic	0.000025
166.	c.3580G>A	p.A1194T	missense	1	VUS	0.000008
167.	c.1540A>G	p.I514V	missense	1	VUS	0.000008
168.	c.2163delC	p.Glu722ArgfsX32	frameshift	1	Pathogenic	0.000000
169.	c.2938C>T	p.R980C	missense	1	VUS	0.000062
170.	c.2308+1G>A		essential splice site	1	Pathogenic	0.000000
171.	c.2170C>T	p.R724W	missense	1	VUS	0.000019
172.	c.2533C>T	p.R845C	missense	1	VUS favour pathogenic	0.000000
173.	c.3676C>T	p.R1226C	missense	1	VUS	0.000058
174.	c.1358C>T	p.P453L	missense	1	VUS	0.000008
175.	c.3049G>A	p.E1017K	missense	1	VUS favour benign	0.000085
176.	c.431_432delGT	p.Gly144AlafsX8	frameshift	1	Pathogenic	0.000000
177.	c.1294G>A	p.A432T	missense	1	VUS	0.000037
178.	c.2525A>G	p.Y842C	missense	1	VUS	0.000000
179.	c.2013_2016delinsGG	p.Pro672AspfsX20	frameshift	1	Pathogenic	0.000000
180.	c.3G>C	p.Met1?	missense	1	Likely Pathogenic	0.000000
181.	c.2557G>A	p.G853S	missense	1	VUS	0.000008
182.	c.2737+2T>A		essential splice site	1	Pathogenic	0.000000
183.	c.2993A>G	p.Q998R	missense	1	VUS favour pathogenic	0.000000
184.	c.3605G>A	p.C1202Y	missense	1	Likely Pathogenic	0.000000
185.	c.3811C>T	p.R1271X	nonsense	1	Pathogenic	0.000025
186.	c.566T>A	p.V189D	missense	1	VUS	0.000000
187.	c.3040delC	p.Leu1014TrpfsX6	frameshift	1	Pathogenic	0.000000
188.	c.655-1G>A		essential splice site	1	Pathogenic	0.000000
189.	c.2436G>T	p.K812N	missense	1	VUS	0.000000
190.	c.2671C>T	p.R891W	missense	1	Likely Pathogenic	0.000031
191.	c.2953A>T	p.K985X	nonsense	1	Pathogenic	0.000000
192.	c.613C>T	p.Q205X	nonsense	1	Pathogenic	0.000000
193.	c.3776delA		frameshift	1	Pathogenic	0.000000
194.	c.1213A>G	p.M405V	missense	1	Pathogenic	0.000000
195.	c.3332_3335dupAGTG	p.W1112X	nonsense	1	Pathogenic	0.000000
196.	c.3753T>G	p.Y1251X	nonsense	1	Pathogenic	0.000000
197.	c.2641G>A	p.V881I	missense	1	VUS	0.000018
198.	c.1535T>A	p.L512Q	missense	1	VUS favour pathogenic	0.000000
199.	c.1892delT		frameshift	1	Pathogenic	0.000000
200.	c.3742G>A	p.G1248R	missense	1	VUS	0.000033
201.	c.103C>T	p.R35W	missense	1	VUS	0.000056
202.	c.2654C>T	p.T885M	missense	1	VUS	0.000022
203.	c.3373G>A	p.V1125M	missense	1	VUS favour pathogenic	0.000022
204.	c.1586C>G	p.T529S	missense	1	VUS favour pathogenic	0.000000
205.	c.3548T>G	p.F1183C	missense	1	Likely Pathogenic	0.000000
206.	c.3286G>T	p.E1096X	nonsense	1	Pathogenic	0.000000
207.	c.3791G>A	p.C1264Y	missense	1	VUS	0.000008
208.	c.966G>A	p.W322X	nonsense	1	Pathogenic	0.000000
209.	c.2737+1G>C		essential splice site	1	Pathogenic	0.000000
210.	c.3277G>T	p.G1093C	missense	1	VUS	0.000020
211.	c.2048G>A	p.W683X	nonsense	1	Pathogenic	0.000000
212.	c.2534_2538delGCGTC		frameshift	1	Pathogenic	0.000000
213.	c.3288delG		frameshift	1	Pathogenic	0.000000
214.	c.1678delG	p.Asp560ThrfsX19	frameshift	1	Pathogenic	0.000000
215.	c.2556_2557delinsTCT	p.Gly853fs	frameshift	1	Pathogenic	0.000000
216.	c.2517_2538del	p.Val840ThrfsX32	frameshift	1	Pathogenic	0.000000
217.	c.2149-1G>A		essential splice site	1	Pathogenic	0.000000
218.	c.821+1G>C		essential splice site	1	Pathogenic	0.000000
219.	c.2524_2525insT	p.Tyr842LeufsX42	frameshift	1	Pathogenic	0.000000
220.	c.1156G>T	p.E386X	nonsense	1	Pathogenic	0.000000
221.	c.333_334insT	p.E112X	nonsense	1	Pathogenic	0.000000
222.	c.2906-2A>G		essential splice site	1	Pathogenic	0.000000
223.	c.533delT	p.Val178GlyfsX7	frameshift	1	Pathogenic	0.000000
224.	c.1628delA		frameshift	1	Pathogenic	0.000000
225.	c.1090+1G>A		essential splice site	1	Pathogenic	0.000000
226.	c.1778C>T	p.S593F	missense	1	VUS favour pathogenic	0.000034
227.	c.1672G>A	p.A558T	missense	1	VUS	0.000008
228.	c.2312T>C	p.V771A	missense	1	VUS	0.000000
229.	c.2518G>A	p.V840M	missense	1	VUS	0.000016
230.	c.3083C>G	p.T1028S	missense	1	VUS	0.000000
231.	c.2528_2536delAGATGCGCG	p.Glu843_Arg845del	inframe	1	Pathogenic	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.290C>T	p.A97V	missense	1	VUS favour pathogenic	0.000000
235.	c.373G>T	p.A125S	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.