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.2670G>A	p.W890X	nonsense	7	Pathogenic	0.000000
13.	c.2827C>T	p.R943X	nonsense	7	Pathogenic	0.000017
14.	c.442G>A	p.G148R	missense	7	VUS favour pathogenic	0.000042
15.	c.1505G>A	p.R502Q	missense	6	Pathogenic	0.000000
16.	c.2308G>A	p.D770N	missense	6	Likely Pathogenic	0.000008
17.	c.2864_2865delCT		frameshift	6	Pathogenic	0.000000
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.821+1G>A		essential splice site	4	Pathogenic	0.000043
22.	c.2905+1G>A		essential splice site	4	Pathogenic	0.000000
23.	c.2454G>A	p.W818X	nonsense	4	Pathogenic	0.000000
24.	c.2182G>T	p.E728X	nonsense	4	Pathogenic	0.000000
25.	c.2096delC		frameshift	4	Pathogenic	0.000000
26.	c.26-2A>G		essential splice site	4	Pathogenic	0.000051
27.	c.2573G>A	p.S858N	missense	4	VUS favour pathogenic	0.000000
28.	c.1483C>G	p.R495G	missense	4	Likely Pathogenic	0.000000
29.	c.3742_3759dup	p.Gly1248_Cys1253dup	inframe	4	Likely Pathogenic	0.000000
30.	c.3064C>T	p.R1022C	missense	4	VUS favour pathogenic	0.000008
31.	c.2450G>A	p.R817Q	missense	3	VUS favour pathogenic	0.000016
32.	c.1591G>A	p.G531R	missense	3	VUS favour pathogenic	0.000017
33.	c.710A>C	p.Y237S	missense	3	Likely Pathogenic	0.000000
34.	c.3190+1G>A		essential splice site	3	Pathogenic	0.000000
35.	c.2920C>T	p.Q974X	nonsense	3	Pathogenic	0.000000
36.	c.355G>A	p.E119K	missense	3	VUS	0.000000
37.	c.3491-2A>T		essential splice site	3	Pathogenic	0.000000
38.	c.2873C>T	p.T958I	missense	3	VUS favour benign	0.000065
39.	c.2311_2312insG	p.Val771GlyfsX62	frameshift	3	Pathogenic	0.000000
40.	c.3233G>A	p.W1078X	nonsense	3	Pathogenic	0.000022
41.	c.3767_3769delCCA	p.Thr1256del	inframe	3	Likely Pathogenic	0.000000
42.	c.1828G>A	p.D610N	missense	3	VUS	0.000000
43.	c.2905C>T	p.Q969X	nonsense	3	Pathogenic	0.000000
44.	c.3624_3625insC	p.Lys1209GlnfsX33	frameshift	2	Pathogenic	0.000000
45.	c.999C>G	p.Y333X	nonsense	2	Pathogenic	0.000000
46.	c.1766G>A	p.R589H	missense	2	VUS	0.000000
47.	c.1895delT	p.Met632ArgfsX31	frameshift	2	Pathogenic	0.000000
48.	c.2882C>T	p.P961L	missense	2	VUS	0.000048
49.	c.1037G>A	p.R346H	missense	2	VUS	0.000000
50.	c.2558delG		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.772+1G>A		essential splice site	2	Pathogenic	0.000000
54.	c.2604_2605delinsA	p.S871fs	frameshift	2	Pathogenic	0.000000
55.	c.436_437insA	p.Thr146AsnfsX7	frameshift	2	Pathogenic	0.000000
56.	c.3624delC		frameshift	2	Pathogenic	0.000000
57.	c.1934C>T	p.P645L	missense	2	VUS	0.000000
58.	c.814C>T	p.R272C	missense	2	VUS	0.000083
59.	c.927-2A>G		essential splice site	2	Pathogenic	0.000000
60.	c.2320G>A	p.A774T	missense	2	VUS	0.000000
61.	c.1897+1G>A		essential splice site	2	Pathogenic	0.000000
62.	c.2943_2947delGACCA		frameshift	2	Pathogenic	0.000000
63.	c.1828G>C	p.D610H	missense	2	VUS favour benign	0.000058
64.	c.532G>A	p.V178M	missense	2	VUS favour pathogenic	0.000020
65.	c.1357_1358delCC		frameshift	2	Pathogenic	0.000000
66.	c.3627+1G>A		essential splice site	2	Pathogenic	0.000000
67.	c.1863delC	p.Phe621LeufsX42	frameshift	2	Pathogenic	0.000000
68.	c.1513_1515delAAG		inframe	2	VUS favour pathogenic	0.000000
69.	c.636C>G	p.S212R	missense	2	VUS favour pathogenic	0.000000
70.	c.3192_3193insC	p.Lys1065GlnfsX12	frameshift	2	Pathogenic	0.000000
71.	c.1210C>T	p.Q404X	nonsense	2	Pathogenic	0.000000
72.	c.3190+2T>G		essential splice site	2	Pathogenic	0.000016
73.	c.1869C>A	p.C623X	nonsense	2	Pathogenic	0.000000
74.	c.2610_2611insC	p.Ser871GlnfsX13	frameshift	1	Pathogenic	0.000000
75.	c.3065G>A	p.R1022H	missense	1	VUS favour pathogenic	0.000000
76.	c.833delG	p.Gly278GlufsX22	frameshift	1	Pathogenic	0.000000
77.	c.853G>A	p.D285N	missense	1	VUS	0.000000
78.	c.3694A>T	p.K1232X	nonsense	1	Pathogenic	0.000000
79.	c.3281A>T	p.N1094I	missense	1	VUS	0.000000
80.	c.1778C>T	p.S593F	missense	1	VUS favour pathogenic	0.000034
81.	c.1418T>C	p.F473S	missense	1	VUS	0.000000
82.	c.2518G>A	p.V840M	missense	1	VUS	0.000016
83.	c.655-1G>A		essential splice site	1	Pathogenic	0.000000
84.	c.3811C>T	p.R1271X	nonsense	1	Pathogenic	0.000025
85.	c.3413G>C	p.R1138P	missense	1	VUS	0.000000
86.	c.3373G>A	p.V1125M	missense	1	VUS favour pathogenic	0.000022
87.	c.1672G>A	p.A558T	missense	1	VUS	0.000008
88.	c.2312T>C	p.V771A	missense	1	VUS	0.000000
89.	c.2210C>T	p.T737M	missense	1	VUS	0.000050
90.	c.373G>T	p.A125S	missense	1	VUS	0.000000
91.	c.3083C>G	p.T1028S	missense	1	VUS	0.000000
92.	c.2671C>T	p.R891W	missense	1	Likely Pathogenic	0.000031
93.	c.3776delA		frameshift	1	Pathogenic	0.000000
94.	c.2534_2538delGCGTC		frameshift	1	Pathogenic	0.000000
95.	c.3415G>A	p.V1139I	missense	1	VUS	0.000087
96.	c.1999_2000delinsG	p.Leu667AspfsX15	frameshift	1	Pathogenic	0.000000
97.	c.1000G>T	p.E334X	nonsense	1	Pathogenic	0.000000
98.	c.2723A>G	p.Y908C	missense	1	VUS	0.000062
99.	c.1693A>T	p.K565X	nonsense	1	Pathogenic	0.000000
100.	c.1699_1700delGA	p.Glu567GlyfsX4	frameshift	1	Pathogenic	0.000000
101.	c.1090+1G>T		essential splice site	1	Pathogenic	0.000000
102.	c.1351+1G>A		essential splice site	1	Pathogenic	0.000000
103.	c.2394_2395insT	p.Gly799TrpfsX34	frameshift	1	Pathogenic	0.000000
104.	c.3166_3167insG	p.Ala1056GlyfsX9	frameshift	1	Pathogenic	0.000000
105.	c.2780_2781delCA		frameshift	1	Pathogenic	0.000000
106.	c.2747G>A	p.W916X	nonsense	1	Pathogenic	0.000000
107.	c.821+2T>C		essential splice site	1	Pathogenic	0.000000
108.	c.2163delC	p.Glu722ArgfsX32	frameshift	1	Pathogenic	0.000000
109.	c.3476_3479dupTTAT	p.Pro1161TyrfsX9	frameshift	1	Pathogenic	0.000000
110.	c.3335G>A	p.W1112X	nonsense	1	Pathogenic	0.000000
111.	c.3408C>A	p.Y1136X	nonsense	1	Pathogenic	0.000000
112.	c.2533C>T	p.R845C	missense	1	VUS favour pathogenic	0.000000
113.	c.2965G>T	p.E989X	nonsense	1	Pathogenic	0.000000
114.	c.459delC		frameshift	1	Pathogenic	0.000000
115.	c.2013_2016delinsGG	p.Pro672AspfsX20	frameshift	1	Pathogenic	0.000000
116.	c.3763G>A	p.A1255T	missense	1	VUS favour pathogenic	0.000075
117.	c.431_432delGT	p.Gly144AlafsX8	frameshift	1	Pathogenic	0.000000
118.	c.2525A>G	p.Y842C	missense	1	VUS	0.000000
119.	c.932C>T	p.S311L	missense	1	VUS	0.000000
120.	c.566T>A	p.V189D	missense	1	VUS	0.000000
121.	c.1397T>A	p.M466K	missense	1	VUS	0.000008
122.	c.2197C>T	p.R733C	missense	1	VUS	0.000085
123.	c.2436G>T	p.K812N	missense	1	VUS	0.000000
124.	c.2269G>A	p.V757M	missense	1	VUS	0.000066
125.	c.3288delG		frameshift	1	Pathogenic	0.000000
126.	c.1960C>T	p.R654C	missense	1	VUS favour benign	0.000008
127.	c.2308+1G>T		essential splice site	1	Pathogenic	0.000000
128.	c.2828G>A	p.R943Q	missense	1	VUS	0.000025
129.	c.3286G>T	p.E1096X	nonsense	1	Pathogenic	0.000000
130.	c.1038_1042dupCGGCA		frameshift	1	Pathogenic	0.000008
131.	c.1624+2T>C		essential splice site	1	Pathogenic	0.000000
132.	c.1090+1G>A		essential splice site	1	Pathogenic	0.000000
133.	c.104G>A	p.R35Q	missense	1	VUS	0.000079
134.	c.3825A>G	p.X1275TrpextX77	nonsense	1	Likely Pathogenic	0.000000
135.	c.451G>A	p.D151N	missense	1	VUS	0.000041
136.	c.177_187del	p.Glu60AlafsX49	frameshift	1	Pathogenic	0.000000
137.	c.1458-1G>A		essential splice site	1	Pathogenic	0.000000
138.	c.1213A>G	p.M405V	missense	1	Pathogenic	0.000000
139.	c.3331-1G>A		essential splice site	1	Pathogenic	0.000000
140.	c.1586C>G	p.T529S	missense	1	VUS favour pathogenic	0.000000
141.	c.1892delT		frameshift	1	Pathogenic	0.000000
142.	c.551_552insT	p.Lys185GlufsX56	frameshift	1	Pathogenic	0.000000
143.	c.2541C>A	p.Y847X	nonsense	1	Pathogenic	0.000000
144.	c.3548T>G	p.F1183C	missense	1	Likely Pathogenic	0.000000
145.	c.966G>A	p.W322X	nonsense	1	Pathogenic	0.000000
146.	c.1505G>T	p.R502L	missense	1	VUS favour pathogenic	0.000000
147.	c.3065G>C	p.R1022P	missense	1	VUS favour pathogenic	0.000025
148.	c.3181C>T	p.Q1061X	nonsense	1	Pathogenic	0.000016
149.	c.2517_2538del	p.Val840ThrfsX32	frameshift	1	Pathogenic	0.000000
150.	c.223G>A	p.D75N	missense	1	VUS favour pathogenic	0.000091
151.	c.713G>A	p.R238H	missense	1	VUS	0.000074
152.	c.1591G>C	p.G531R	missense	1	VUS favour pathogenic	0.000017
153.	c.2560A>G	p.M854V	missense	1	VUS	0.000000
154.	c.1575T>G	p.Y525X	nonsense	1	Pathogenic	0.000000
155.	c.844C>T	p.R282W	missense	1	VUS favour pathogenic	0.000000
156.	c.2833_2834delCG		frameshift	1	Pathogenic	0.000000
157.	c.3746G>T	p.G1249V	missense	1	VUS	0.000000
158.	c.1800delA		frameshift	1	Pathogenic	0.000000
159.	c.2905+1G>C		essential splice site	1	Pathogenic	0.000000
160.	c.3098G>A	p.R1033Q	missense	1	VUS	0.000000
161.	c.3735delC		frameshift	1	Likely Pathogenic	0.000000
162.	c.1156G>T	p.E386X	nonsense	1	Pathogenic	0.000000
163.	c.2113_2114insA	p.Thr705AsnfsX3	frameshift	1	Pathogenic	0.000000
164.	c.1351+2T>C		essential splice site	1	Pathogenic	0.000000
165.	c.3068_3069insA	p.Asn1023LysfsX28	frameshift	1	Pathogenic	0.000000
166.	c.2875_2876delAC	p.Thr959GlyfsX91	frameshift	1	Pathogenic	0.000000
167.	c.1628delA		frameshift	1	Pathogenic	0.000000
168.	c.3690_3691delCA	p.Phe1230LeufsX11	frameshift	1	Pathogenic	0.000000
169.	c.2437A>T	p.K813X	nonsense	1	Pathogenic	0.000000
170.	c.3253G>T	p.E1085X	nonsense	1	Pathogenic	0.000000
171.	c.3476_3477delTT		frameshift	1	Pathogenic	0.000000
172.	c.290C>T	p.A97V	missense	1	VUS favour pathogenic	0.000000
173.	c.993_994insT	p.E332X	nonsense	1	Pathogenic	0.000000
174.	c.2528_2536delAGATGCGCG	p.Glu843_Arg845del	inframe	1	Pathogenic	0.000000
175.	c.2234A>G	p.D745G	missense	1	VUS	0.000000
176.	c.326C>T	p.A109V	missense	1	VUS	0.000000
177.	c.1021G>A	p.G341S	missense	1	VUS favour pathogenic	0.000025
178.	c.2040_2041insT	p.Val681CysfsX12	frameshift	1	Pathogenic	0.000000
179.	c.3580G>A	p.A1194T	missense	1	VUS	0.000008
180.	c.1188G>T	p.W396C	missense	1	VUS	0.000000
181.	c.436A>C	p.T146P	missense	1	VUS	0.000000
182.	c.481C>A	p.P161T	missense	1	VUS favour pathogenic	0.000041
183.	c.506-1G>T		essential splice site	1	Pathogenic	0.000000
184.	c.931T>A	p.S311T	missense	1	VUS	0.000000
185.	c.2459G>A	p.R820Q	missense	1	Likely Pathogenic	0.000016
186.	c.1540A>G	p.I514V	missense	1	VUS	0.000008
187.	c.3676C>T	p.R1226C	missense	1	VUS	0.000058
188.	c.1358C>T	p.P453L	missense	1	VUS	0.000008
189.	c.932C>A	p.S311X	nonsense	1	Pathogenic	0.000000
190.	c.3049G>A	p.E1017K	missense	1	VUS favour benign	0.000085
191.	c.1343T>C	p.F448S	missense	1	Likely Pathogenic	0.000000
192.	c.1168delC		frameshift	1	Pathogenic	0.000000
193.	c.2938C>T	p.R980C	missense	1	VUS	0.000062
194.	c.2170C>T	p.R724W	missense	1	VUS	0.000019
195.	c.3G>C	p.Met1?	missense	1	Likely Pathogenic	0.000000
196.	c.2557G>A	p.G853S	missense	1	VUS	0.000008
197.	c.1294G>A	p.A432T	missense	1	VUS	0.000037
198.	c.3040delC	p.Leu1014TrpfsX6	frameshift	1	Pathogenic	0.000000
199.	c.2490_2491insT	p.His831SerfsTer2	frameshift	1	Pathogenic	0.000024
200.	c.2737+2T>A		essential splice site	1	Pathogenic	0.000000
201.	c.3605G>A	p.C1202Y	missense	1	Likely Pathogenic	0.000000
202.	c.1224-2A>G		essential splice site	1	Pathogenic	0.000000
203.	c.613C>T	p.Q205X	nonsense	1	Pathogenic	0.000000
204.	c.3332_3335dupAGTG	p.W1112X	nonsense	1	Pathogenic	0.000000
205.	c.1841A>G	p.Y614C	missense	1	VUS favour pathogenic	0.000000
206.	c.2953A>T	p.K985X	nonsense	1	Pathogenic	0.000000
207.	c.2641G>A	p.V881I	missense	1	VUS	0.000018
208.	c.2939G>A	p.R980H	missense	1	VUS	0.000000
209.	c.1535T>A	p.L512Q	missense	1	VUS favour pathogenic	0.000000
210.	c.3815-1G>A		essential splice site	1	Pathogenic	0.000000
211.	c.2449C>T	p.R817W	missense	1	VUS	0.000000
212.	c.3753T>G	p.Y1251X	nonsense	1	Pathogenic	0.000000
213.	c.1950C>G	p.D650E	missense	1	VUS	0.000000
214.	c.3742G>A	p.G1248R	missense	1	VUS	0.000033
215.	c.518C>A	p.T173N	missense	1	VUS	0.000000
216.	c.1456T>G	p.W486G	missense	1	Likely Pathogenic	0.000000
217.	c.2308+1G>A		essential splice site	1	Pathogenic	0.000000
218.	c.103C>T	p.R35W	missense	1	VUS	0.000056
219.	c.2993A>G	p.Q998R	missense	1	VUS favour pathogenic	0.000000
220.	c.2654C>T	p.T885M	missense	1	VUS	0.000022
221.	c.2737+1G>C		essential splice site	1	Pathogenic	0.000000
222.	c.3277G>T	p.G1093C	missense	1	VUS	0.000020
223.	c.3797G>A	p.C1266Y	missense	1	Likely Pathogenic	0.000000
224.	c.1273C>T	p.Q425X	nonsense	1	Pathogenic	0.000000
225.	c.3791G>A	p.C1264Y	missense	1	VUS	0.000008
226.	c.2048G>A	p.W683X	nonsense	1	Pathogenic	0.000000
227.	c.2556_2557delinsTCT	p.Gly853fs	frameshift	1	Pathogenic	0.000000
228.	c.2149-1G>A		essential splice site	1	Pathogenic	0.000000
229.	c.821+1G>C		essential splice site	1	Pathogenic	0.000000
230.	c.1678delG	p.Asp560ThrfsX19	frameshift	1	Pathogenic	0.000000
231.	c.1924C>T	p.Q642X	nonsense	1	Pathogenic	0.000000
232.	c.2906-2A>G		essential splice site	1	Pathogenic	0.000000
233.	c.533delT	p.Val178GlyfsX7	frameshift	1	Pathogenic	0.000000
234.	c.2524_2525insT	p.Tyr842LeufsX42	frameshift	1	Pathogenic	0.000000
235.	c.333_334insT	p.E112X	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.