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