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