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