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