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