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.655G>C	p.V219L	missense	8	Likely Pathogenic	0.000000
11.	c.2429G>A	p.R810H	missense	8	VUS favour pathogenic	0.000033
12.	c.442G>A	p.G148R	missense	7	VUS favour pathogenic	0.000042
13.	c.2827C>T	p.R943X	nonsense	7	Pathogenic	0.000017
14.	c.2670G>A	p.W890X	nonsense	7	Pathogenic	0.000000
15.	c.2864_2865delCT		frameshift	6	Pathogenic	0.000000
16.	c.2308G>A	p.D770N	missense	6	Likely Pathogenic	0.000008
17.	c.3226_3227insT		frameshift	6	Pathogenic	0.000000
18.	c.1505G>A	p.R502Q	missense	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.3742_3759dup	p.Gly1248_Cys1253dup	inframe	4	Likely Pathogenic	0.000000
22.	c.2573G>A	p.S858N	missense	4	VUS favour 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.2454G>A	p.W818X	nonsense	4	Pathogenic	0.000000
29.	c.3064C>T	p.R1022C	missense	4	VUS favour pathogenic	0.000008
30.	c.2182G>T	p.E728X	nonsense	4	Pathogenic	0.000000
31.	c.3233G>A	p.W1078X	nonsense	3	Pathogenic	0.000022
32.	c.2311_2312insG	p.Val771GlyfsX62	frameshift	3	Pathogenic	0.000000
33.	c.1828G>A	p.D610N	missense	3	VUS	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.2873C>T	p.T958I	missense	3	VUS favour benign	0.000065
37.	c.1591G>A	p.G531R	missense	3	VUS favour pathogenic	0.000017
38.	c.3767_3769delCCA	p.Thr1256del	inframe	3	Likely Pathogenic	0.000000
39.	c.2905C>T	p.Q969X	nonsense	3	Pathogenic	0.000000
40.	c.2920C>T	p.Q974X	nonsense	3	Pathogenic	0.000000
41.	c.710A>C	p.Y237S	missense	3	Likely Pathogenic	0.000000
42.	c.2450G>A	p.R817Q	missense	3	VUS favour pathogenic	0.000016
43.	c.3491-2A>T		essential splice site	3	Pathogenic	0.000000
44.	c.2882C>T	p.P961L	missense	2	VUS	0.000048
45.	c.1037G>A	p.R346H	missense	2	VUS	0.000000
46.	c.1863delC	p.Phe621LeufsX42	frameshift	2	Pathogenic	0.000000
47.	c.532G>A	p.V178M	missense	2	VUS favour pathogenic	0.000020
48.	c.1210C>T	p.Q404X	nonsense	2	Pathogenic	0.000000
49.	c.3190+2T>G		essential splice site	2	Pathogenic	0.000016
50.	c.1869C>A	p.C623X	nonsense	2	Pathogenic	0.000000
51.	c.436_437insA	p.Thr146AsnfsX7	frameshift	2	Pathogenic	0.000000
52.	c.3624delC		frameshift	2	Pathogenic	0.000000
53.	c.1934C>T	p.P645L	missense	2	VUS	0.000000
54.	c.3192_3193insC	p.Lys1065GlnfsX12	frameshift	2	Pathogenic	0.000000
55.	c.3624_3625insC	p.Lys1209GlnfsX33	frameshift	2	Pathogenic	0.000000
56.	c.999C>G	p.Y333X	nonsense	2	Pathogenic	0.000000
57.	c.1766G>A	p.R589H	missense	2	VUS	0.000000
58.	c.1513_1515delAAG		inframe	2	VUS favour pathogenic	0.000000
59.	c.636C>G	p.S212R	missense	2	VUS favour pathogenic	0.000000
60.	c.1895delT	p.Met632ArgfsX31	frameshift	2	Pathogenic	0.000000
61.	c.1357_1358delCC		frameshift	2	Pathogenic	0.000000
62.	c.3627+1G>A		essential splice site	2	Pathogenic	0.000000
63.	c.772+1G>A		essential splice site	2	Pathogenic	0.000000
64.	c.2604_2605delinsA	p.S871fs	frameshift	2	Pathogenic	0.000000
65.	c.814C>T	p.R272C	missense	2	VUS	0.000083
66.	c.1790G>A	p.R597Q	missense	2	VUS favour pathogenic	0.000000
67.	c.1483C>T	p.R495W	missense	2	VUS favour pathogenic	0.000000
68.	c.2320G>A	p.A774T	missense	2	VUS	0.000000
69.	c.2943_2947delGACCA		frameshift	2	Pathogenic	0.000000
70.	c.1897+1G>A		essential splice site	2	Pathogenic	0.000000
71.	c.927-2A>G		essential splice site	2	Pathogenic	0.000000
72.	c.2558delG		frameshift	2	Pathogenic	0.000000
73.	c.1828G>C	p.D610H	missense	2	VUS favour benign	0.000058
74.	c.2170C>T	p.R724W	missense	1	VUS	0.000019
75.	c.3408C>A	p.Y1136X	nonsense	1	Pathogenic	0.000000
76.	c.3735delC		frameshift	1	Likely Pathogenic	0.000000
77.	c.2533C>T	p.R845C	missense	1	VUS favour pathogenic	0.000000
78.	c.3676C>T	p.R1226C	missense	1	VUS	0.000058
79.	c.1358C>T	p.P453L	missense	1	VUS	0.000008
80.	c.2490_2491insT	p.His831SerfsTer2	frameshift	1	Pathogenic	0.000024
81.	c.3049G>A	p.E1017K	missense	1	VUS favour benign	0.000085
82.	c.1224-2A>G		essential splice site	1	Pathogenic	0.000000
83.	c.2163delC	p.Glu722ArgfsX32	frameshift	1	Pathogenic	0.000000
84.	c.2308+1G>A		essential splice site	1	Pathogenic	0.000000
85.	c.2938C>T	p.R980C	missense	1	VUS	0.000062
86.	c.431_432delGT	p.Gly144AlafsX8	frameshift	1	Pathogenic	0.000000
87.	c.1294G>A	p.A432T	missense	1	VUS	0.000037
88.	c.459delC		frameshift	1	Pathogenic	0.000000
89.	c.2525A>G	p.Y842C	missense	1	VUS	0.000000
90.	c.2013_2016delinsGG	p.Pro672AspfsX20	frameshift	1	Pathogenic	0.000000
91.	c.3G>C	p.Met1?	missense	1	Likely Pathogenic	0.000000
92.	c.2557G>A	p.G853S	missense	1	VUS	0.000008
93.	c.3763G>A	p.A1255T	missense	1	VUS favour pathogenic	0.000075
94.	c.1960C>T	p.R654C	missense	1	VUS favour benign	0.000008
95.	c.566T>A	p.V189D	missense	1	VUS	0.000000
96.	c.3040delC	p.Leu1014TrpfsX6	frameshift	1	Pathogenic	0.000000
97.	c.2197C>T	p.R733C	missense	1	VUS	0.000085
98.	c.2436G>T	p.K812N	missense	1	VUS	0.000000
99.	c.2737+2T>A		essential splice site	1	Pathogenic	0.000000
100.	c.3605G>A	p.C1202Y	missense	1	Likely Pathogenic	0.000000
101.	c.2953A>T	p.K985X	nonsense	1	Pathogenic	0.000000
102.	c.613C>T	p.Q205X	nonsense	1	Pathogenic	0.000000
103.	c.2308+1G>T		essential splice site	1	Pathogenic	0.000000
104.	c.3332_3335dupAGTG	p.W1112X	nonsense	1	Pathogenic	0.000000
105.	c.1168delC		frameshift	1	Pathogenic	0.000000
106.	c.1535T>A	p.L512Q	missense	1	VUS favour pathogenic	0.000000
107.	c.1624+2T>C		essential splice site	1	Pathogenic	0.000000
108.	c.3742G>A	p.G1248R	missense	1	VUS	0.000033
109.	c.2654C>T	p.T885M	missense	1	VUS	0.000022
110.	c.932C>A	p.S311X	nonsense	1	Pathogenic	0.000000
111.	c.3373G>A	p.V1125M	missense	1	VUS favour pathogenic	0.000022
112.	c.1343T>C	p.F448S	missense	1	Likely Pathogenic	0.000000
113.	c.1586C>G	p.T529S	missense	1	VUS favour pathogenic	0.000000
114.	c.103C>T	p.R35W	missense	1	VUS	0.000056
115.	c.1924C>T	p.Q642X	nonsense	1	Pathogenic	0.000000
116.	c.3791G>A	p.C1264Y	missense	1	VUS	0.000008
117.	c.966G>A	p.W322X	nonsense	1	Pathogenic	0.000000
118.	c.2737+1G>C		essential splice site	1	Pathogenic	0.000000
119.	c.3277G>T	p.G1093C	missense	1	VUS	0.000020
120.	c.2534_2538delGCGTC		frameshift	1	Pathogenic	0.000000
121.	c.3548T>G	p.F1183C	missense	1	Likely Pathogenic	0.000000
122.	c.1678delG	p.Asp560ThrfsX19	frameshift	1	Pathogenic	0.000000
123.	c.2556_2557delinsTCT	p.Gly853fs	frameshift	1	Pathogenic	0.000000
124.	c.3181C>T	p.Q1061X	nonsense	1	Pathogenic	0.000016
125.	c.2517_2538del	p.Val840ThrfsX32	frameshift	1	Pathogenic	0.000000
126.	c.2149-1G>A		essential splice site	1	Pathogenic	0.000000
127.	c.821+1G>C		essential splice site	1	Pathogenic	0.000000
128.	c.223G>A	p.D75N	missense	1	VUS favour pathogenic	0.000091
129.	c.333_334insT	p.E112X	nonsense	1	Pathogenic	0.000000
130.	c.2906-2A>G		essential splice site	1	Pathogenic	0.000000
131.	c.533delT	p.Val178GlyfsX7	frameshift	1	Pathogenic	0.000000
132.	c.2524_2525insT	p.Tyr842LeufsX42	frameshift	1	Pathogenic	0.000000
133.	c.1800delA		frameshift	1	Pathogenic	0.000000
134.	c.1273C>T	p.Q425X	nonsense	1	Pathogenic	0.000000
135.	c.1672G>A	p.A558T	missense	1	VUS	0.000008
136.	c.1456T>G	p.W486G	missense	1	Likely Pathogenic	0.000000
137.	c.2518G>A	p.V840M	missense	1	VUS	0.000016
138.	c.1090+1G>T		essential splice site	1	Pathogenic	0.000000
139.	c.1351+1G>A		essential splice site	1	Pathogenic	0.000000
140.	c.2528_2536delAGATGCGCG	p.Glu843_Arg845del	inframe	1	Pathogenic	0.000000
141.	c.3415G>A	p.V1139I	missense	1	VUS	0.000087
142.	c.2210C>T	p.T737M	missense	1	VUS	0.000050
143.	c.3476_3477delTT		frameshift	1	Pathogenic	0.000000
144.	c.3797G>A	p.C1266Y	missense	1	Likely Pathogenic	0.000000
145.	c.290C>T	p.A97V	missense	1	VUS favour pathogenic	0.000000
146.	c.373G>T	p.A125S	missense	1	VUS	0.000000
147.	c.2780_2781delCA		frameshift	1	Pathogenic	0.000000
148.	c.3083C>G	p.T1028S	missense	1	VUS	0.000000
149.	c.481C>A	p.P161T	missense	1	VUS favour pathogenic	0.000041
150.	c.436A>C	p.T146P	missense	1	VUS	0.000000
151.	c.506-1G>T		essential splice site	1	Pathogenic	0.000000
152.	c.1999_2000delinsG	p.Leu667AspfsX15	frameshift	1	Pathogenic	0.000000
153.	c.1021G>A	p.G341S	missense	1	VUS favour pathogenic	0.000025
154.	c.326C>T	p.A109V	missense	1	VUS	0.000000
155.	c.2040_2041insT	p.Val681CysfsX12	frameshift	1	Pathogenic	0.000000
156.	c.1000G>T	p.E334X	nonsense	1	Pathogenic	0.000000
157.	c.2723A>G	p.Y908C	missense	1	VUS	0.000062
158.	c.3580G>A	p.A1194T	missense	1	VUS	0.000008
159.	c.3335G>A	p.W1112X	nonsense	1	Pathogenic	0.000000
160.	c.1188G>T	p.W396C	missense	1	VUS	0.000000
161.	c.1699_1700delGA	p.Glu567GlyfsX4	frameshift	1	Pathogenic	0.000000
162.	c.2747G>A	p.W916X	nonsense	1	Pathogenic	0.000000
163.	c.2394_2395insT	p.Gly799TrpfsX34	frameshift	1	Pathogenic	0.000000
164.	c.931T>A	p.S311T	missense	1	VUS	0.000000
165.	c.3166_3167insG	p.Ala1056GlyfsX9	frameshift	1	Pathogenic	0.000000
166.	c.2965G>T	p.E989X	nonsense	1	Pathogenic	0.000000
167.	c.821+2T>C		essential splice site	1	Pathogenic	0.000000
168.	c.3476_3479dupTTAT	p.Pro1161TyrfsX9	frameshift	1	Pathogenic	0.000000
169.	c.2269G>A	p.V757M	missense	1	VUS	0.000066
170.	c.3811C>T	p.R1271X	nonsense	1	Pathogenic	0.000025
171.	c.932C>T	p.S311L	missense	1	VUS	0.000000
172.	c.1397T>A	p.M466K	missense	1	VUS	0.000008
173.	c.655-1G>A		essential splice site	1	Pathogenic	0.000000
174.	c.2993A>G	p.Q998R	missense	1	VUS favour pathogenic	0.000000
175.	c.3776delA		frameshift	1	Pathogenic	0.000000
176.	c.2828G>A	p.R943Q	missense	1	VUS	0.000025
177.	c.1213A>G	p.M405V	missense	1	Pathogenic	0.000000
178.	c.2671C>T	p.R891W	missense	1	Likely Pathogenic	0.000031
179.	c.1841A>G	p.Y614C	missense	1	VUS favour pathogenic	0.000000
180.	c.2449C>T	p.R817W	missense	1	VUS	0.000000
181.	c.3825A>G	p.X1275TrpextX77	nonsense	1	Likely Pathogenic	0.000000
182.	c.451G>A	p.D151N	missense	1	VUS	0.000041
183.	c.2641G>A	p.V881I	missense	1	VUS	0.000018
184.	c.2939G>A	p.R980H	missense	1	VUS	0.000000
185.	c.1892delT		frameshift	1	Pathogenic	0.000000
186.	c.3815-1G>A		essential splice site	1	Pathogenic	0.000000
187.	c.2833_2834delCG		frameshift	1	Pathogenic	0.000000
188.	c.104G>A	p.R35Q	missense	1	VUS	0.000079
189.	c.3753T>G	p.Y1251X	nonsense	1	Pathogenic	0.000000
190.	c.518C>A	p.T173N	missense	1	VUS	0.000000
191.	c.177_187del	p.Glu60AlafsX49	frameshift	1	Pathogenic	0.000000
192.	c.1950C>G	p.D650E	missense	1	VUS	0.000000
193.	c.1458-1G>A		essential splice site	1	Pathogenic	0.000000
194.	c.551_552insT	p.Lys185GlufsX56	frameshift	1	Pathogenic	0.000000
195.	c.2541C>A	p.Y847X	nonsense	1	Pathogenic	0.000000
196.	c.3331-1G>A		essential splice site	1	Pathogenic	0.000000
197.	c.1505G>T	p.R502L	missense	1	VUS favour pathogenic	0.000000
198.	c.2048G>A	p.W683X	nonsense	1	Pathogenic	0.000000
199.	c.3286G>T	p.E1096X	nonsense	1	Pathogenic	0.000000
200.	c.3288delG		frameshift	1	Pathogenic	0.000000
201.	c.1156G>T	p.E386X	nonsense	1	Pathogenic	0.000000
202.	c.2459G>A	p.R820Q	missense	1	Likely Pathogenic	0.000016
203.	c.713G>A	p.R238H	missense	1	VUS	0.000074
204.	c.2560A>G	p.M854V	missense	1	VUS	0.000000
205.	c.2905+1G>C		essential splice site	1	Pathogenic	0.000000
206.	c.3098G>A	p.R1033Q	missense	1	VUS	0.000000
207.	c.1628delA		frameshift	1	Pathogenic	0.000000
208.	c.2610_2611insC	p.Ser871GlnfsX13	frameshift	1	Pathogenic	0.000000
209.	c.1090+1G>A		essential splice site	1	Pathogenic	0.000000
210.	c.3065G>A	p.R1022H	missense	1	VUS favour pathogenic	0.000000
211.	c.3746G>T	p.G1249V	missense	1	VUS	0.000000
212.	c.833delG	p.Gly278GlufsX22	frameshift	1	Pathogenic	0.000000
213.	c.1418T>C	p.F473S	missense	1	VUS	0.000000
214.	c.3068_3069insA	p.Asn1023LysfsX28	frameshift	1	Pathogenic	0.000000
215.	c.853G>A	p.D285N	missense	1	VUS	0.000000
216.	c.3694A>T	p.K1232X	nonsense	1	Pathogenic	0.000000
217.	c.2113_2114insA	p.Thr705AsnfsX3	frameshift	1	Pathogenic	0.000000
218.	c.1778C>T	p.S593F	missense	1	VUS favour pathogenic	0.000034
219.	c.3281A>T	p.N1094I	missense	1	VUS	0.000000
220.	c.1351+2T>C		essential splice site	1	Pathogenic	0.000000
221.	c.2312T>C	p.V771A	missense	1	VUS	0.000000
222.	c.2875_2876delAC	p.Thr959GlyfsX91	frameshift	1	Pathogenic	0.000000
223.	c.3690_3691delCA	p.Phe1230LeufsX11	frameshift	1	Pathogenic	0.000000
224.	c.2437A>T	p.K813X	nonsense	1	Pathogenic	0.000000
225.	c.3413G>C	p.R1138P	missense	1	VUS	0.000000
226.	c.3253G>T	p.E1085X	nonsense	1	Pathogenic	0.000000
227.	c.993_994insT	p.E332X	nonsense	1	Pathogenic	0.000000
228.	c.1693A>T	p.K565X	nonsense	1	Pathogenic	0.000000
229.	c.2234A>G	p.D745G	missense	1	VUS	0.000000
230.	c.3065G>C	p.R1022P	missense	1	VUS favour pathogenic	0.000025
231.	c.844C>T	p.R282W	missense	1	VUS favour pathogenic	0.000000
232.	c.1038_1042dupCGGCA		frameshift	1	Pathogenic	0.000008
233.	c.1591G>C	p.G531R	missense	1	VUS favour pathogenic	0.000017
234.	c.1540A>G	p.I514V	missense	1	VUS	0.000008
235.	c.1575T>G	p.Y525X	nonsense	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.