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