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.1505G>A	p.R502Q	missense	6	Pathogenic	0.000000
16.	c.2864_2865delCT		frameshift	6	Pathogenic	0.000000
17.	c.2308G>A	p.D770N	missense	6	Likely Pathogenic	0.000008
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.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.2920C>T	p.Q974X	nonsense	3	Pathogenic	0.000000
32.	c.2905C>T	p.Q969X	nonsense	3	Pathogenic	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.3491-2A>T		essential splice site	3	Pathogenic	0.000000
36.	c.3233G>A	p.W1078X	nonsense	3	Pathogenic	0.000022
37.	c.2311_2312insG	p.Val771GlyfsX62	frameshift	3	Pathogenic	0.000000
38.	c.1828G>A	p.D610N	missense	3	VUS	0.000000
39.	c.355G>A	p.E119K	missense	3	VUS	0.000000
40.	c.3190+1G>A		essential splice site	3	Pathogenic	0.000000
41.	c.2873C>T	p.T958I	missense	3	VUS favour benign	0.000065
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.814C>T	p.R272C	missense	2	VUS	0.000083
45.	c.1483C>T	p.R495W	missense	2	VUS favour pathogenic	0.000000
46.	c.1790G>A	p.R597Q	missense	2	VUS favour pathogenic	0.000000
47.	c.2943_2947delGACCA		frameshift	2	Pathogenic	0.000000
48.	c.2320G>A	p.A774T	missense	2	VUS	0.000000
49.	c.1897+1G>A		essential splice site	2	Pathogenic	0.000000
50.	c.927-2A>G		essential splice site	2	Pathogenic	0.000000
51.	c.2558delG		frameshift	2	Pathogenic	0.000000
52.	c.1828G>C	p.D610H	missense	2	VUS favour benign	0.000058
53.	c.2882C>T	p.P961L	missense	2	VUS	0.000048
54.	c.1037G>A	p.R346H	missense	2	VUS	0.000000
55.	c.1863delC	p.Phe621LeufsX42	frameshift	2	Pathogenic	0.000000
56.	c.532G>A	p.V178M	missense	2	VUS favour pathogenic	0.000020
57.	c.1210C>T	p.Q404X	nonsense	2	Pathogenic	0.000000
58.	c.3624delC		frameshift	2	Pathogenic	0.000000
59.	c.3190+2T>G		essential splice site	2	Pathogenic	0.000016
60.	c.1869C>A	p.C623X	nonsense	2	Pathogenic	0.000000
61.	c.436_437insA	p.Thr146AsnfsX7	frameshift	2	Pathogenic	0.000000
62.	c.1934C>T	p.P645L	missense	2	VUS	0.000000
63.	c.3192_3193insC	p.Lys1065GlnfsX12	frameshift	2	Pathogenic	0.000000
64.	c.999C>G	p.Y333X	nonsense	2	Pathogenic	0.000000
65.	c.3624_3625insC	p.Lys1209GlnfsX33	frameshift	2	Pathogenic	0.000000
66.	c.1513_1515delAAG		inframe	2	VUS favour pathogenic	0.000000
67.	c.1766G>A	p.R589H	missense	2	VUS	0.000000
68.	c.636C>G	p.S212R	missense	2	VUS favour pathogenic	0.000000
69.	c.1895delT	p.Met632ArgfsX31	frameshift	2	Pathogenic	0.000000
70.	c.3627+1G>A		essential splice site	2	Pathogenic	0.000000
71.	c.1357_1358delCC		frameshift	2	Pathogenic	0.000000
72.	c.772+1G>A		essential splice site	2	Pathogenic	0.000000
73.	c.2604_2605delinsA	p.S871fs	frameshift	2	Pathogenic	0.000000
74.	c.551_552insT	p.Lys185GlufsX56	frameshift	1	Pathogenic	0.000000
75.	c.2541C>A	p.Y847X	nonsense	1	Pathogenic	0.000000
76.	c.3331-1G>A		essential splice site	1	Pathogenic	0.000000
77.	c.3286G>T	p.E1096X	nonsense	1	Pathogenic	0.000000
78.	c.1505G>T	p.R502L	missense	1	VUS favour pathogenic	0.000000
79.	c.2048G>A	p.W683X	nonsense	1	Pathogenic	0.000000
80.	c.3288delG		frameshift	1	Pathogenic	0.000000
81.	c.713G>A	p.R238H	missense	1	VUS	0.000074
82.	c.2560A>G	p.M854V	missense	1	VUS	0.000000
83.	c.1156G>T	p.E386X	nonsense	1	Pathogenic	0.000000
84.	c.2459G>A	p.R820Q	missense	1	Likely Pathogenic	0.000016
85.	c.3746G>T	p.G1249V	missense	1	VUS	0.000000
86.	c.833delG	p.Gly278GlufsX22	frameshift	1	Pathogenic	0.000000
87.	c.2905+1G>C		essential splice site	1	Pathogenic	0.000000
88.	c.3098G>A	p.R1033Q	missense	1	VUS	0.000000
89.	c.1628delA		frameshift	1	Pathogenic	0.000000
90.	c.2610_2611insC	p.Ser871GlnfsX13	frameshift	1	Pathogenic	0.000000
91.	c.1090+1G>A		essential splice site	1	Pathogenic	0.000000
92.	c.3065G>A	p.R1022H	missense	1	VUS favour pathogenic	0.000000
93.	c.3281A>T	p.N1094I	missense	1	VUS	0.000000
94.	c.1351+2T>C		essential splice site	1	Pathogenic	0.000000
95.	c.1418T>C	p.F473S	missense	1	VUS	0.000000
96.	c.3068_3069insA	p.Asn1023LysfsX28	frameshift	1	Pathogenic	0.000000
97.	c.853G>A	p.D285N	missense	1	VUS	0.000000
98.	c.3694A>T	p.K1232X	nonsense	1	Pathogenic	0.000000
99.	c.2113_2114insA	p.Thr705AsnfsX3	frameshift	1	Pathogenic	0.000000
100.	c.1778C>T	p.S593F	missense	1	VUS favour pathogenic	0.000034
101.	c.3413G>C	p.R1138P	missense	1	VUS	0.000000
102.	c.3253G>T	p.E1085X	nonsense	1	Pathogenic	0.000000
103.	c.2312T>C	p.V771A	missense	1	VUS	0.000000
104.	c.2875_2876delAC	p.Thr959GlyfsX91	frameshift	1	Pathogenic	0.000000
105.	c.3690_3691delCA	p.Phe1230LeufsX11	frameshift	1	Pathogenic	0.000000
106.	c.2437A>T	p.K813X	nonsense	1	Pathogenic	0.000000
107.	c.993_994insT	p.E332X	nonsense	1	Pathogenic	0.000000
108.	c.1693A>T	p.K565X	nonsense	1	Pathogenic	0.000000
109.	c.2234A>G	p.D745G	missense	1	VUS	0.000000
110.	c.3065G>C	p.R1022P	missense	1	VUS favour pathogenic	0.000025
111.	c.844C>T	p.R282W	missense	1	VUS favour pathogenic	0.000000
112.	c.1591G>C	p.G531R	missense	1	VUS favour pathogenic	0.000017
113.	c.1540A>G	p.I514V	missense	1	VUS	0.000008
114.	c.1575T>G	p.Y525X	nonsense	1	Pathogenic	0.000000
115.	c.1038_1042dupCGGCA		frameshift	1	Pathogenic	0.000008
116.	c.1224-2A>G		essential splice site	1	Pathogenic	0.000000
117.	c.2163delC	p.Glu722ArgfsX32	frameshift	1	Pathogenic	0.000000
118.	c.2308+1G>A		essential splice site	1	Pathogenic	0.000000
119.	c.2938C>T	p.R980C	missense	1	VUS	0.000062
120.	c.2170C>T	p.R724W	missense	1	VUS	0.000019
121.	c.3408C>A	p.Y1136X	nonsense	1	Pathogenic	0.000000
122.	c.3735delC		frameshift	1	Likely Pathogenic	0.000000
123.	c.2533C>T	p.R845C	missense	1	VUS favour pathogenic	0.000000
124.	c.3676C>T	p.R1226C	missense	1	VUS	0.000058
125.	c.1358C>T	p.P453L	missense	1	VUS	0.000008
126.	c.2490_2491insT	p.His831SerfsTer2	frameshift	1	Pathogenic	0.000024
127.	c.3049G>A	p.E1017K	missense	1	VUS favour benign	0.000085
128.	c.3763G>A	p.A1255T	missense	1	VUS favour pathogenic	0.000075
129.	c.431_432delGT	p.Gly144AlafsX8	frameshift	1	Pathogenic	0.000000
130.	c.1294G>A	p.A432T	missense	1	VUS	0.000037
131.	c.459delC		frameshift	1	Pathogenic	0.000000
132.	c.2525A>G	p.Y842C	missense	1	VUS	0.000000
133.	c.2013_2016delinsGG	p.Pro672AspfsX20	frameshift	1	Pathogenic	0.000000
134.	c.3G>C	p.Met1?	missense	1	Likely Pathogenic	0.000000
135.	c.2557G>A	p.G853S	missense	1	VUS	0.000008
136.	c.2436G>T	p.K812N	missense	1	VUS	0.000000
137.	c.2737+2T>A		essential splice site	1	Pathogenic	0.000000
138.	c.3605G>A	p.C1202Y	missense	1	Likely Pathogenic	0.000000
139.	c.1960C>T	p.R654C	missense	1	VUS favour benign	0.000008
140.	c.566T>A	p.V189D	missense	1	VUS	0.000000
141.	c.3040delC	p.Leu1014TrpfsX6	frameshift	1	Pathogenic	0.000000
142.	c.2197C>T	p.R733C	missense	1	VUS	0.000085
143.	c.2953A>T	p.K985X	nonsense	1	Pathogenic	0.000000
144.	c.613C>T	p.Q205X	nonsense	1	Pathogenic	0.000000
145.	c.2308+1G>T		essential splice site	1	Pathogenic	0.000000
146.	c.3332_3335dupAGTG	p.W1112X	nonsense	1	Pathogenic	0.000000
147.	c.1624+2T>C		essential splice site	1	Pathogenic	0.000000
148.	c.1168delC		frameshift	1	Pathogenic	0.000000
149.	c.1535T>A	p.L512Q	missense	1	VUS favour pathogenic	0.000000
150.	c.3742G>A	p.G1248R	missense	1	VUS	0.000033
151.	c.1586C>G	p.T529S	missense	1	VUS favour pathogenic	0.000000
152.	c.103C>T	p.R35W	missense	1	VUS	0.000056
153.	c.1924C>T	p.Q642X	nonsense	1	Pathogenic	0.000000
154.	c.2654C>T	p.T885M	missense	1	VUS	0.000022
155.	c.932C>A	p.S311X	nonsense	1	Pathogenic	0.000000
156.	c.3373G>A	p.V1125M	missense	1	VUS favour pathogenic	0.000022
157.	c.1343T>C	p.F448S	missense	1	Likely Pathogenic	0.000000
158.	c.3548T>G	p.F1183C	missense	1	Likely Pathogenic	0.000000
159.	c.3791G>A	p.C1264Y	missense	1	VUS	0.000008
160.	c.966G>A	p.W322X	nonsense	1	Pathogenic	0.000000
161.	c.2737+1G>C		essential splice site	1	Pathogenic	0.000000
162.	c.3277G>T	p.G1093C	missense	1	VUS	0.000020
163.	c.2534_2538delGCGTC		frameshift	1	Pathogenic	0.000000
164.	c.2517_2538del	p.Val840ThrfsX32	frameshift	1	Pathogenic	0.000000
165.	c.2149-1G>A		essential splice site	1	Pathogenic	0.000000
166.	c.821+1G>C		essential splice site	1	Pathogenic	0.000000
167.	c.223G>A	p.D75N	missense	1	VUS favour pathogenic	0.000091
168.	c.1678delG	p.Asp560ThrfsX19	frameshift	1	Pathogenic	0.000000
169.	c.2556_2557delinsTCT	p.Gly853fs	frameshift	1	Pathogenic	0.000000
170.	c.3181C>T	p.Q1061X	nonsense	1	Pathogenic	0.000016
171.	c.533delT	p.Val178GlyfsX7	frameshift	1	Pathogenic	0.000000
172.	c.2524_2525insT	p.Tyr842LeufsX42	frameshift	1	Pathogenic	0.000000
173.	c.333_334insT	p.E112X	nonsense	1	Pathogenic	0.000000
174.	c.2906-2A>G		essential splice site	1	Pathogenic	0.000000
175.	c.1800delA		frameshift	1	Pathogenic	0.000000
176.	c.1273C>T	p.Q425X	nonsense	1	Pathogenic	0.000000
177.	c.2518G>A	p.V840M	missense	1	VUS	0.000016
178.	c.1090+1G>T		essential splice site	1	Pathogenic	0.000000
179.	c.1672G>A	p.A558T	missense	1	VUS	0.000008
180.	c.1456T>G	p.W486G	missense	1	Likely Pathogenic	0.000000
181.	c.3083C>G	p.T1028S	missense	1	VUS	0.000000
182.	c.1351+1G>A		essential splice site	1	Pathogenic	0.000000
183.	c.2528_2536delAGATGCGCG	p.Glu843_Arg845del	inframe	1	Pathogenic	0.000000
184.	c.3415G>A	p.V1139I	missense	1	VUS	0.000087
185.	c.2210C>T	p.T737M	missense	1	VUS	0.000050
186.	c.3476_3477delTT		frameshift	1	Pathogenic	0.000000
187.	c.3797G>A	p.C1266Y	missense	1	Likely Pathogenic	0.000000
188.	c.290C>T	p.A97V	missense	1	VUS favour pathogenic	0.000000
189.	c.373G>T	p.A125S	missense	1	VUS	0.000000
190.	c.2780_2781delCA		frameshift	1	Pathogenic	0.000000
191.	c.2723A>G	p.Y908C	missense	1	VUS	0.000062
192.	c.3580G>A	p.A1194T	missense	1	VUS	0.000008
193.	c.3335G>A	p.W1112X	nonsense	1	Pathogenic	0.000000
194.	c.1188G>T	p.W396C	missense	1	VUS	0.000000
195.	c.1699_1700delGA	p.Glu567GlyfsX4	frameshift	1	Pathogenic	0.000000
196.	c.481C>A	p.P161T	missense	1	VUS favour pathogenic	0.000041
197.	c.436A>C	p.T146P	missense	1	VUS	0.000000
198.	c.506-1G>T		essential splice site	1	Pathogenic	0.000000
199.	c.1999_2000delinsG	p.Leu667AspfsX15	frameshift	1	Pathogenic	0.000000
200.	c.1021G>A	p.G341S	missense	1	VUS favour pathogenic	0.000025
201.	c.326C>T	p.A109V	missense	1	VUS	0.000000
202.	c.2040_2041insT	p.Val681CysfsX12	frameshift	1	Pathogenic	0.000000
203.	c.1000G>T	p.E334X	nonsense	1	Pathogenic	0.000000
204.	c.3166_3167insG	p.Ala1056GlyfsX9	frameshift	1	Pathogenic	0.000000
205.	c.2747G>A	p.W916X	nonsense	1	Pathogenic	0.000000
206.	c.2394_2395insT	p.Gly799TrpfsX34	frameshift	1	Pathogenic	0.000000
207.	c.931T>A	p.S311T	missense	1	VUS	0.000000
208.	c.3476_3479dupTTAT	p.Pro1161TyrfsX9	frameshift	1	Pathogenic	0.000000
209.	c.2965G>T	p.E989X	nonsense	1	Pathogenic	0.000000
210.	c.821+2T>C		essential splice site	1	Pathogenic	0.000000
211.	c.655-1G>A		essential splice site	1	Pathogenic	0.000000
212.	c.2993A>G	p.Q998R	missense	1	VUS favour pathogenic	0.000000
213.	c.2269G>A	p.V757M	missense	1	VUS	0.000066
214.	c.3811C>T	p.R1271X	nonsense	1	Pathogenic	0.000025
215.	c.932C>T	p.S311L	missense	1	VUS	0.000000
216.	c.1397T>A	p.M466K	missense	1	VUS	0.000008
217.	c.2671C>T	p.R891W	missense	1	Likely Pathogenic	0.000031
218.	c.1841A>G	p.Y614C	missense	1	VUS favour pathogenic	0.000000
219.	c.3776delA		frameshift	1	Pathogenic	0.000000
220.	c.2828G>A	p.R943Q	missense	1	VUS	0.000025
221.	c.1213A>G	p.M405V	missense	1	Pathogenic	0.000000
222.	c.1892delT		frameshift	1	Pathogenic	0.000000
223.	c.3815-1G>A		essential splice site	1	Pathogenic	0.000000
224.	c.2833_2834delCG		frameshift	1	Pathogenic	0.000000
225.	c.104G>A	p.R35Q	missense	1	VUS	0.000079
226.	c.3753T>G	p.Y1251X	nonsense	1	Pathogenic	0.000000
227.	c.2449C>T	p.R817W	missense	1	VUS	0.000000
228.	c.3825A>G	p.X1275TrpextX77	nonsense	1	Likely Pathogenic	0.000000
229.	c.451G>A	p.D151N	missense	1	VUS	0.000041
230.	c.2641G>A	p.V881I	missense	1	VUS	0.000018
231.	c.2939G>A	p.R980H	missense	1	VUS	0.000000
232.	c.518C>A	p.T173N	missense	1	VUS	0.000000
233.	c.177_187del	p.Glu60AlafsX49	frameshift	1	Pathogenic	0.000000
234.	c.1950C>G	p.D650E	missense	1	VUS	0.000000
235.	c.1458-1G>A		essential splice site	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.