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.442G>A	p.G148R	missense	7	VUS favour pathogenic	0.000042
13.	c.2670G>A	p.W890X	nonsense	7	Pathogenic	0.000000
14.	c.2827C>T	p.R943X	nonsense	7	Pathogenic	0.000017
15.	c.1505G>A	p.R502Q	missense	6	Pathogenic	0.000000
16.	c.2864_2865delCT		frameshift	6	Pathogenic	0.000000
17.	c.3226_3227insT		frameshift	6	Pathogenic	0.000000
18.	c.2308G>A	p.D770N	missense	6	Likely Pathogenic	0.000008
19.	c.913_914delTT		frameshift	5	Pathogenic	0.000000
20.	c.2374T>C	p.W792R	missense	5	Likely Pathogenic	0.000000
21.	c.26-2A>G		essential splice site	4	Pathogenic	0.000051
22.	c.2573G>A	p.S858N	missense	4	VUS favour pathogenic	0.000000
23.	c.2454G>A	p.W818X	nonsense	4	Pathogenic	0.000000
24.	c.2096delC		frameshift	4	Pathogenic	0.000000
25.	c.3064C>T	p.R1022C	missense	4	VUS favour pathogenic	0.000008
26.	c.2182G>T	p.E728X	nonsense	4	Pathogenic	0.000000
27.	c.3742_3759dup	p.Gly1248_Cys1253dup	inframe	4	Likely Pathogenic	0.000000
28.	c.1483C>G	p.R495G	missense	4	Likely Pathogenic	0.000000
29.	c.821+1G>A		essential splice site	4	Pathogenic	0.000043
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.2873C>T	p.T958I	missense	3	VUS favour benign	0.000065
33.	c.2920C>T	p.Q974X	nonsense	3	Pathogenic	0.000000
34.	c.355G>A	p.E119K	missense	3	VUS	0.000000
35.	c.3190+1G>A		essential splice site	3	Pathogenic	0.000000
36.	c.2450G>A	p.R817Q	missense	3	VUS favour pathogenic	0.000016
37.	c.1828G>A	p.D610N	missense	3	VUS	0.000000
38.	c.3491-2A>T		essential splice site	3	Pathogenic	0.000000
39.	c.3233G>A	p.W1078X	nonsense	3	Pathogenic	0.000022
40.	c.710A>C	p.Y237S	missense	3	Likely Pathogenic	0.000000
41.	c.2905C>T	p.Q969X	nonsense	3	Pathogenic	0.000000
42.	c.2311_2312insG	p.Val771GlyfsX62	frameshift	3	Pathogenic	0.000000
43.	c.3767_3769delCCA	p.Thr1256del	inframe	3	Likely Pathogenic	0.000000
44.	c.927-2A>G		essential splice site	2	Pathogenic	0.000000
45.	c.814C>T	p.R272C	missense	2	VUS	0.000083
46.	c.1210C>T	p.Q404X	nonsense	2	Pathogenic	0.000000
47.	c.1869C>A	p.C623X	nonsense	2	Pathogenic	0.000000
48.	c.999C>G	p.Y333X	nonsense	2	Pathogenic	0.000000
49.	c.772+1G>A		essential splice site	2	Pathogenic	0.000000
50.	c.3624_3625insC	p.Lys1209GlnfsX33	frameshift	2	Pathogenic	0.000000
51.	c.532G>A	p.V178M	missense	2	VUS favour pathogenic	0.000020
52.	c.1895delT	p.Met632ArgfsX31	frameshift	2	Pathogenic	0.000000
53.	c.1828G>C	p.D610H	missense	2	VUS favour benign	0.000058
54.	c.2320G>A	p.A774T	missense	2	VUS	0.000000
55.	c.1037G>A	p.R346H	missense	2	VUS	0.000000
56.	c.636C>G	p.S212R	missense	2	VUS favour pathogenic	0.000000
57.	c.2604_2605delinsA	p.S871fs	frameshift	2	Pathogenic	0.000000
58.	c.436_437insA	p.Thr146AsnfsX7	frameshift	2	Pathogenic	0.000000
59.	c.2943_2947delGACCA		frameshift	2	Pathogenic	0.000000
60.	c.1934C>T	p.P645L	missense	2	VUS	0.000000
61.	c.2558delG		frameshift	2	Pathogenic	0.000000
62.	c.3627+1G>A		essential splice site	2	Pathogenic	0.000000
63.	c.1790G>A	p.R597Q	missense	2	VUS favour pathogenic	0.000000
64.	c.1766G>A	p.R589H	missense	2	VUS	0.000000
65.	c.1897+1G>A		essential splice site	2	Pathogenic	0.000000
66.	c.3192_3193insC	p.Lys1065GlnfsX12	frameshift	2	Pathogenic	0.000000
67.	c.1357_1358delCC		frameshift	2	Pathogenic	0.000000
68.	c.2882C>T	p.P961L	missense	2	VUS	0.000048
69.	c.1483C>T	p.R495W	missense	2	VUS favour pathogenic	0.000000
70.	c.1863delC	p.Phe621LeufsX42	frameshift	2	Pathogenic	0.000000
71.	c.3624delC		frameshift	2	Pathogenic	0.000000
72.	c.3190+2T>G		essential splice site	2	Pathogenic	0.000016
73.	c.1513_1515delAAG		inframe	2	VUS favour pathogenic	0.000000
74.	c.223G>A	p.D75N	missense	1	VUS favour pathogenic	0.000091
75.	c.2048G>A	p.W683X	nonsense	1	Pathogenic	0.000000
76.	c.2149-1G>A		essential splice site	1	Pathogenic	0.000000
77.	c.844C>T	p.R282W	missense	1	VUS favour pathogenic	0.000000
78.	c.1678delG	p.Asp560ThrfsX19	frameshift	1	Pathogenic	0.000000
79.	c.1397T>A	p.M466K	missense	1	VUS	0.000008
80.	c.2556_2557delinsTCT	p.Gly853fs	frameshift	1	Pathogenic	0.000000
81.	c.3181C>T	p.Q1061X	nonsense	1	Pathogenic	0.000016
82.	c.1343T>C	p.F448S	missense	1	Likely Pathogenic	0.000000
83.	c.533delT	p.Val178GlyfsX7	frameshift	1	Pathogenic	0.000000
84.	c.2524_2525insT	p.Tyr842LeufsX42	frameshift	1	Pathogenic	0.000000
85.	c.2828G>A	p.R943Q	missense	1	VUS	0.000025
86.	c.333_334insT	p.E112X	nonsense	1	Pathogenic	0.000000
87.	c.2906-2A>G		essential splice site	1	Pathogenic	0.000000
88.	c.713G>A	p.R238H	missense	1	VUS	0.000074
89.	c.451G>A	p.D151N	missense	1	VUS	0.000041
90.	c.833delG	p.Gly278GlufsX22	frameshift	1	Pathogenic	0.000000
91.	c.2610_2611insC	p.Ser871GlnfsX13	frameshift	1	Pathogenic	0.000000
92.	c.104G>A	p.R35Q	missense	1	VUS	0.000079
93.	c.3065G>A	p.R1022H	missense	1	VUS favour pathogenic	0.000000
94.	c.2780_2781delCA		frameshift	1	Pathogenic	0.000000
95.	c.3281A>T	p.N1094I	missense	1	VUS	0.000000
96.	c.1418T>C	p.F473S	missense	1	VUS	0.000000
97.	c.3476_3477delTT		frameshift	1	Pathogenic	0.000000
98.	c.1458-1G>A		essential splice site	1	Pathogenic	0.000000
99.	c.853G>A	p.D285N	missense	1	VUS	0.000000
100.	c.3694A>T	p.K1232X	nonsense	1	Pathogenic	0.000000
101.	c.3335G>A	p.W1112X	nonsense	1	Pathogenic	0.000000
102.	c.3413G>C	p.R1138P	missense	1	VUS	0.000000
103.	c.2308+1G>A		essential splice site	1	Pathogenic	0.000000
104.	c.1021G>A	p.G341S	missense	1	VUS favour pathogenic	0.000025
105.	c.2308+1G>T		essential splice site	1	Pathogenic	0.000000
106.	c.3580G>A	p.A1194T	missense	1	VUS	0.000008
107.	c.2993A>G	p.Q998R	missense	1	VUS favour pathogenic	0.000000
108.	c.1090+1G>T		essential splice site	1	Pathogenic	0.000000
109.	c.481C>A	p.P161T	missense	1	VUS favour pathogenic	0.000041
110.	c.1456T>G	p.W486G	missense	1	Likely Pathogenic	0.000000
111.	c.1999_2000delinsG	p.Leu667AspfsX15	frameshift	1	Pathogenic	0.000000
112.	c.2234A>G	p.D745G	missense	1	VUS	0.000000
113.	c.1168delC		frameshift	1	Pathogenic	0.000000
114.	c.1693A>T	p.K565X	nonsense	1	Pathogenic	0.000000
115.	c.1000G>T	p.E334X	nonsense	1	Pathogenic	0.000000
116.	c.3166_3167insG	p.Ala1056GlyfsX9	frameshift	1	Pathogenic	0.000000
117.	c.1351+1G>A		essential splice site	1	Pathogenic	0.000000
118.	c.2747G>A	p.W916X	nonsense	1	Pathogenic	0.000000
119.	c.3797G>A	p.C1266Y	missense	1	Likely Pathogenic	0.000000
120.	c.2394_2395insT	p.Gly799TrpfsX34	frameshift	1	Pathogenic	0.000000
121.	c.2560A>G	p.M854V	missense	1	VUS	0.000000
122.	c.2905+1G>C		essential splice site	1	Pathogenic	0.000000
123.	c.3098G>A	p.R1033Q	missense	1	VUS	0.000000
124.	c.2163delC	p.Glu722ArgfsX32	frameshift	1	Pathogenic	0.000000
125.	c.3476_3479dupTTAT	p.Pro1161TyrfsX9	frameshift	1	Pathogenic	0.000000
126.	c.2533C>T	p.R845C	missense	1	VUS favour pathogenic	0.000000
127.	c.2965G>T	p.E989X	nonsense	1	Pathogenic	0.000000
128.	c.1358C>T	p.P453L	missense	1	VUS	0.000008
129.	c.3746G>T	p.G1249V	missense	1	VUS	0.000000
130.	c.821+2T>C		essential splice site	1	Pathogenic	0.000000
131.	c.3068_3069insA	p.Asn1023LysfsX28	frameshift	1	Pathogenic	0.000000
132.	c.431_432delGT	p.Gly144AlafsX8	frameshift	1	Pathogenic	0.000000
133.	c.2525A>G	p.Y842C	missense	1	VUS	0.000000
134.	c.2013_2016delinsGG	p.Pro672AspfsX20	frameshift	1	Pathogenic	0.000000
135.	c.3288delG		frameshift	1	Pathogenic	0.000000
136.	c.3373G>A	p.V1125M	missense	1	VUS favour pathogenic	0.000022
137.	c.2436G>T	p.K812N	missense	1	VUS	0.000000
138.	c.3753T>G	p.Y1251X	nonsense	1	Pathogenic	0.000000
139.	c.566T>A	p.V189D	missense	1	VUS	0.000000
140.	c.2534_2538delGCGTC		frameshift	1	Pathogenic	0.000000
141.	c.655-1G>A		essential splice site	1	Pathogenic	0.000000
142.	c.1624+2T>C		essential splice site	1	Pathogenic	0.000000
143.	c.3825A>G	p.X1275TrpextX77	nonsense	1	Likely Pathogenic	0.000000
144.	c.2641G>A	p.V881I	missense	1	VUS	0.000018
145.	c.2671C>T	p.R891W	missense	1	Likely Pathogenic	0.000031
146.	c.3742G>A	p.G1248R	missense	1	VUS	0.000033
147.	c.1273C>T	p.Q425X	nonsense	1	Pathogenic	0.000000
148.	c.177_187del	p.Glu60AlafsX49	frameshift	1	Pathogenic	0.000000
149.	c.1213A>G	p.M405V	missense	1	Pathogenic	0.000000
150.	c.1540A>G	p.I514V	missense	1	VUS	0.000008
151.	c.2170C>T	p.R724W	missense	1	VUS	0.000019
152.	c.1586C>G	p.T529S	missense	1	VUS favour pathogenic	0.000000
153.	c.103C>T	p.R35W	missense	1	VUS	0.000056
154.	c.3676C>T	p.R1226C	missense	1	VUS	0.000058
155.	c.551_552insT	p.Lys185GlufsX56	frameshift	1	Pathogenic	0.000000
156.	c.2541C>A	p.Y847X	nonsense	1	Pathogenic	0.000000
157.	c.3049G>A	p.E1017K	missense	1	VUS favour benign	0.000085
158.	c.3331-1G>A		essential splice site	1	Pathogenic	0.000000
159.	c.2938C>T	p.R980C	missense	1	VUS	0.000062
160.	c.1892delT		frameshift	1	Pathogenic	0.000000
161.	c.1294G>A	p.A432T	missense	1	VUS	0.000037
162.	c.3548T>G	p.F1183C	missense	1	Likely Pathogenic	0.000000
163.	c.2557G>A	p.G853S	missense	1	VUS	0.000008
164.	c.966G>A	p.W322X	nonsense	1	Pathogenic	0.000000
165.	c.1505G>T	p.R502L	missense	1	VUS favour pathogenic	0.000000
166.	c.2517_2538del	p.Val840ThrfsX32	frameshift	1	Pathogenic	0.000000
167.	c.3065G>C	p.R1022P	missense	1	VUS favour pathogenic	0.000025
168.	c.3605G>A	p.C1202Y	missense	1	Likely Pathogenic	0.000000
169.	c.1778C>T	p.S593F	missense	1	VUS favour pathogenic	0.000034
170.	c.1591G>C	p.G531R	missense	1	VUS favour pathogenic	0.000017
171.	c.3811C>T	p.R1271X	nonsense	1	Pathogenic	0.000025
172.	c.1800delA		frameshift	1	Pathogenic	0.000000
173.	c.1351+2T>C		essential splice site	1	Pathogenic	0.000000
174.	c.3776delA		frameshift	1	Pathogenic	0.000000
175.	c.1038_1042dupCGGCA		frameshift	1	Pathogenic	0.000008
176.	c.1156G>T	p.E386X	nonsense	1	Pathogenic	0.000000
177.	c.2113_2114insA	p.Thr705AsnfsX3	frameshift	1	Pathogenic	0.000000
178.	c.2437A>T	p.K813X	nonsense	1	Pathogenic	0.000000
179.	c.2654C>T	p.T885M	missense	1	VUS	0.000022
180.	c.3253G>T	p.E1085X	nonsense	1	Pathogenic	0.000000
181.	c.2312T>C	p.V771A	missense	1	VUS	0.000000
182.	c.1628delA		frameshift	1	Pathogenic	0.000000
183.	c.2875_2876delAC	p.Thr959GlyfsX91	frameshift	1	Pathogenic	0.000000
184.	c.1090+1G>A		essential splice site	1	Pathogenic	0.000000
185.	c.3690_3691delCA	p.Phe1230LeufsX11	frameshift	1	Pathogenic	0.000000
186.	c.3791G>A	p.C1264Y	missense	1	VUS	0.000008
187.	c.993_994insT	p.E332X	nonsense	1	Pathogenic	0.000000
188.	c.2737+1G>C		essential splice site	1	Pathogenic	0.000000
189.	c.3277G>T	p.G1093C	missense	1	VUS	0.000020
190.	c.2528_2536delAGATGCGCG	p.Glu843_Arg845del	inframe	1	Pathogenic	0.000000
191.	c.290C>T	p.A97V	missense	1	VUS favour pathogenic	0.000000
192.	c.1188G>T	p.W396C	missense	1	VUS	0.000000
193.	c.3408C>A	p.Y1136X	nonsense	1	Pathogenic	0.000000
194.	c.436A>C	p.T146P	missense	1	VUS	0.000000
195.	c.506-1G>T		essential splice site	1	Pathogenic	0.000000
196.	c.2490_2491insT	p.His831SerfsTer2	frameshift	1	Pathogenic	0.000024
197.	c.821+1G>C		essential splice site	1	Pathogenic	0.000000
198.	c.326C>T	p.A109V	missense	1	VUS	0.000000
199.	c.2040_2041insT	p.Val681CysfsX12	frameshift	1	Pathogenic	0.000000
200.	c.459delC		frameshift	1	Pathogenic	0.000000
201.	c.931T>A	p.S311T	missense	1	VUS	0.000000
202.	c.932C>A	p.S311X	nonsense	1	Pathogenic	0.000000
203.	c.2833_2834delCG		frameshift	1	Pathogenic	0.000000
204.	c.3763G>A	p.A1255T	missense	1	VUS favour pathogenic	0.000075
205.	c.1575T>G	p.Y525X	nonsense	1	Pathogenic	0.000000
206.	c.3286G>T	p.E1096X	nonsense	1	Pathogenic	0.000000
207.	c.3G>C	p.Met1?	missense	1	Likely Pathogenic	0.000000
208.	c.1224-2A>G		essential splice site	1	Pathogenic	0.000000
209.	c.1672G>A	p.A558T	missense	1	VUS	0.000008
210.	c.2737+2T>A		essential splice site	1	Pathogenic	0.000000
211.	c.2269G>A	p.V757M	missense	1	VUS	0.000066
212.	c.1960C>T	p.R654C	missense	1	VUS favour benign	0.000008
213.	c.3735delC		frameshift	1	Likely Pathogenic	0.000000
214.	c.932C>T	p.S311L	missense	1	VUS	0.000000
215.	c.2518G>A	p.V840M	missense	1	VUS	0.000016
216.	c.3040delC	p.Leu1014TrpfsX6	frameshift	1	Pathogenic	0.000000
217.	c.2197C>T	p.R733C	missense	1	VUS	0.000085
218.	c.3332_3335dupAGTG	p.W1112X	nonsense	1	Pathogenic	0.000000
219.	c.3415G>A	p.V1139I	missense	1	VUS	0.000087
220.	c.2210C>T	p.T737M	missense	1	VUS	0.000050
221.	c.1841A>G	p.Y614C	missense	1	VUS favour pathogenic	0.000000
222.	c.2953A>T	p.K985X	nonsense	1	Pathogenic	0.000000
223.	c.373G>T	p.A125S	missense	1	VUS	0.000000
224.	c.613C>T	p.Q205X	nonsense	1	Pathogenic	0.000000
225.	c.3083C>G	p.T1028S	missense	1	VUS	0.000000
226.	c.1699_1700delGA	p.Glu567GlyfsX4	frameshift	1	Pathogenic	0.000000
227.	c.3815-1G>A		essential splice site	1	Pathogenic	0.000000
228.	c.1924C>T	p.Q642X	nonsense	1	Pathogenic	0.000000
229.	c.2449C>T	p.R817W	missense	1	VUS	0.000000
230.	c.2723A>G	p.Y908C	missense	1	VUS	0.000062
231.	c.2939G>A	p.R980H	missense	1	VUS	0.000000
232.	c.1535T>A	p.L512Q	missense	1	VUS favour pathogenic	0.000000
233.	c.518C>A	p.T173N	missense	1	VUS	0.000000
234.	c.2459G>A	p.R820Q	missense	1	Likely Pathogenic	0.000016
235.	c.1950C>G	p.D650E	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.