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.2308G>A	p.D770N	missense	6	Likely Pathogenic	0.000008
16.	c.1505G>A	p.R502Q	missense	6	Pathogenic	0.000000
17.	c.3226_3227insT		frameshift	6	Pathogenic	0.000000
18.	c.2864_2865delCT		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.2096delC		frameshift	4	Pathogenic	0.000000
22.	c.3742_3759dup	p.Gly1248_Cys1253dup	inframe	4	Likely Pathogenic	0.000000
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.2905+1G>A		essential splice site	4	Pathogenic	0.000000
26.	c.2573G>A	p.S858N	missense	4	VUS favour pathogenic	0.000000
27.	c.26-2A>G		essential splice site	4	Pathogenic	0.000051
28.	c.2182G>T	p.E728X	nonsense	4	Pathogenic	0.000000
29.	c.2454G>A	p.W818X	nonsense	4	Pathogenic	0.000000
30.	c.3064C>T	p.R1022C	missense	4	VUS favour pathogenic	0.000008
31.	c.710A>C	p.Y237S	missense	3	Likely Pathogenic	0.000000
32.	c.2450G>A	p.R817Q	missense	3	VUS favour pathogenic	0.000016
33.	c.3491-2A>T		essential splice site	3	Pathogenic	0.000000
34.	c.2873C>T	p.T958I	missense	3	VUS favour benign	0.000065
35.	c.2311_2312insG	p.Val771GlyfsX62	frameshift	3	Pathogenic	0.000000
36.	c.3233G>A	p.W1078X	nonsense	3	Pathogenic	0.000022
37.	c.3767_3769delCCA	p.Thr1256del	inframe	3	Likely Pathogenic	0.000000
38.	c.1828G>A	p.D610N	missense	3	VUS	0.000000
39.	c.2905C>T	p.Q969X	nonsense	3	Pathogenic	0.000000
40.	c.3190+1G>A		essential splice site	3	Pathogenic	0.000000
41.	c.1591G>A	p.G531R	missense	3	VUS favour pathogenic	0.000017
42.	c.2920C>T	p.Q974X	nonsense	3	Pathogenic	0.000000
43.	c.355G>A	p.E119K	missense	3	VUS	0.000000
44.	c.2320G>A	p.A774T	missense	2	VUS	0.000000
45.	c.1790G>A	p.R597Q	missense	2	VUS favour pathogenic	0.000000
46.	c.1483C>T	p.R495W	missense	2	VUS favour pathogenic	0.000000
47.	c.2943_2947delGACCA		frameshift	2	Pathogenic	0.000000
48.	c.1897+1G>A		essential splice site	2	Pathogenic	0.000000
49.	c.1828G>C	p.D610H	missense	2	VUS favour benign	0.000058
50.	c.2558delG		frameshift	2	Pathogenic	0.000000
51.	c.1863delC	p.Phe621LeufsX42	frameshift	2	Pathogenic	0.000000
52.	c.3627+1G>A		essential splice site	2	Pathogenic	0.000000
53.	c.532G>A	p.V178M	missense	2	VUS favour pathogenic	0.000020
54.	c.3192_3193insC	p.Lys1065GlnfsX12	frameshift	2	Pathogenic	0.000000
55.	c.1210C>T	p.Q404X	nonsense	2	Pathogenic	0.000000
56.	c.1869C>A	p.C623X	nonsense	2	Pathogenic	0.000000
57.	c.3624delC		frameshift	2	Pathogenic	0.000000
58.	c.3190+2T>G		essential splice site	2	Pathogenic	0.000016
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.1513_1515delAAG		inframe	2	VUS favour pathogenic	0.000000
63.	c.636C>G	p.S212R	missense	2	VUS favour pathogenic	0.000000
64.	c.1895delT	p.Met632ArgfsX31	frameshift	2	Pathogenic	0.000000
65.	c.927-2A>G		essential splice site	2	Pathogenic	0.000000
66.	c.2882C>T	p.P961L	missense	2	VUS	0.000048
67.	c.1037G>A	p.R346H	missense	2	VUS	0.000000
68.	c.1357_1358delCC		frameshift	2	Pathogenic	0.000000
69.	c.772+1G>A		essential splice site	2	Pathogenic	0.000000
70.	c.2604_2605delinsA	p.S871fs	frameshift	2	Pathogenic	0.000000
71.	c.436_437insA	p.Thr146AsnfsX7	frameshift	2	Pathogenic	0.000000
72.	c.814C>T	p.R272C	missense	2	VUS	0.000083
73.	c.1934C>T	p.P645L	missense	2	VUS	0.000000
74.	c.3288delG		frameshift	1	Pathogenic	0.000000
75.	c.3746G>T	p.G1249V	missense	1	VUS	0.000000
76.	c.2905+1G>C		essential splice site	1	Pathogenic	0.000000
77.	c.3098G>A	p.R1033Q	missense	1	VUS	0.000000
78.	c.2113_2114insA	p.Thr705AsnfsX3	frameshift	1	Pathogenic	0.000000
79.	c.1351+2T>C		essential splice site	1	Pathogenic	0.000000
80.	c.1156G>T	p.E386X	nonsense	1	Pathogenic	0.000000
81.	c.3068_3069insA	p.Asn1023LysfsX28	frameshift	1	Pathogenic	0.000000
82.	c.1090+1G>A		essential splice site	1	Pathogenic	0.000000
83.	c.3690_3691delCA	p.Phe1230LeufsX11	frameshift	1	Pathogenic	0.000000
84.	c.2437A>T	p.K813X	nonsense	1	Pathogenic	0.000000
85.	c.3253G>T	p.E1085X	nonsense	1	Pathogenic	0.000000
86.	c.1628delA		frameshift	1	Pathogenic	0.000000
87.	c.2875_2876delAC	p.Thr959GlyfsX91	frameshift	1	Pathogenic	0.000000
88.	c.2459G>A	p.R820Q	missense	1	Likely Pathogenic	0.000016
89.	c.290C>T	p.A97V	missense	1	VUS favour pathogenic	0.000000
90.	c.1778C>T	p.S593F	missense	1	VUS favour pathogenic	0.000034
91.	c.993_994insT	p.E332X	nonsense	1	Pathogenic	0.000000
92.	c.2528_2536delAGATGCGCG	p.Glu843_Arg845del	inframe	1	Pathogenic	0.000000
93.	c.2234A>G	p.D745G	missense	1	VUS	0.000000
94.	c.326C>T	p.A109V	missense	1	VUS	0.000000
95.	c.2040_2041insT	p.Val681CysfsX12	frameshift	1	Pathogenic	0.000000
96.	c.3580G>A	p.A1194T	missense	1	VUS	0.000008
97.	c.1188G>T	p.W396C	missense	1	VUS	0.000000
98.	c.436A>C	p.T146P	missense	1	VUS	0.000000
99.	c.506-1G>T		essential splice site	1	Pathogenic	0.000000
100.	c.931T>A	p.S311T	missense	1	VUS	0.000000
101.	c.1540A>G	p.I514V	missense	1	VUS	0.000008
102.	c.1273C>T	p.Q425X	nonsense	1	Pathogenic	0.000000
103.	c.1358C>T	p.P453L	missense	1	VUS	0.000008
104.	c.1693A>T	p.K565X	nonsense	1	Pathogenic	0.000000
105.	c.3049G>A	p.E1017K	missense	1	VUS favour benign	0.000085
106.	c.3065G>C	p.R1022P	missense	1	VUS favour pathogenic	0.000025
107.	c.2938C>T	p.R980C	missense	1	VUS	0.000062
108.	c.2170C>T	p.R724W	missense	1	VUS	0.000019
109.	c.3676C>T	p.R1226C	missense	1	VUS	0.000058
110.	c.3G>C	p.Met1?	missense	1	Likely Pathogenic	0.000000
111.	c.1038_1042dupCGGCA		frameshift	1	Pathogenic	0.000008
112.	c.2557G>A	p.G853S	missense	1	VUS	0.000008
113.	c.1575T>G	p.Y525X	nonsense	1	Pathogenic	0.000000
114.	c.1591G>C	p.G531R	missense	1	VUS favour pathogenic	0.000017
115.	c.1294G>A	p.A432T	missense	1	VUS	0.000037
116.	c.2490_2491insT	p.His831SerfsTer2	frameshift	1	Pathogenic	0.000024
117.	c.3040delC	p.Leu1014TrpfsX6	frameshift	1	Pathogenic	0.000000
118.	c.1224-2A>G		essential splice site	1	Pathogenic	0.000000
119.	c.2737+2T>A		essential splice site	1	Pathogenic	0.000000
120.	c.3605G>A	p.C1202Y	missense	1	Likely Pathogenic	0.000000
121.	c.3408C>A	p.Y1136X	nonsense	1	Pathogenic	0.000000
122.	c.3735delC		frameshift	1	Likely Pathogenic	0.000000
123.	c.3332_3335dupAGTG	p.W1112X	nonsense	1	Pathogenic	0.000000
124.	c.3763G>A	p.A1255T	missense	1	VUS favour pathogenic	0.000075
125.	c.1841A>G	p.Y614C	missense	1	VUS favour pathogenic	0.000000
126.	c.2953A>T	p.K985X	nonsense	1	Pathogenic	0.000000
127.	c.459delC		frameshift	1	Pathogenic	0.000000
128.	c.613C>T	p.Q205X	nonsense	1	Pathogenic	0.000000
129.	c.2939G>A	p.R980H	missense	1	VUS	0.000000
130.	c.1535T>A	p.L512Q	missense	1	VUS favour pathogenic	0.000000
131.	c.3815-1G>A		essential splice site	1	Pathogenic	0.000000
132.	c.1960C>T	p.R654C	missense	1	VUS favour benign	0.000008
133.	c.2449C>T	p.R817W	missense	1	VUS	0.000000
134.	c.2308+1G>A		essential splice site	1	Pathogenic	0.000000
135.	c.2641G>A	p.V881I	missense	1	VUS	0.000018
136.	c.1950C>G	p.D650E	missense	1	VUS	0.000000
137.	c.3742G>A	p.G1248R	missense	1	VUS	0.000033
138.	c.518C>A	p.T173N	missense	1	VUS	0.000000
139.	c.103C>T	p.R35W	missense	1	VUS	0.000056
140.	c.1624+2T>C		essential splice site	1	Pathogenic	0.000000
141.	c.2654C>T	p.T885M	missense	1	VUS	0.000022
142.	c.3277G>T	p.G1093C	missense	1	VUS	0.000020
143.	c.3791G>A	p.C1264Y	missense	1	VUS	0.000008
144.	c.2737+1G>C		essential splice site	1	Pathogenic	0.000000
145.	c.2556_2557delinsTCT	p.Gly853fs	frameshift	1	Pathogenic	0.000000
146.	c.1343T>C	p.F448S	missense	1	Likely Pathogenic	0.000000
147.	c.2149-1G>A		essential splice site	1	Pathogenic	0.000000
148.	c.932C>A	p.S311X	nonsense	1	Pathogenic	0.000000
149.	c.821+1G>C		essential splice site	1	Pathogenic	0.000000
150.	c.1924C>T	p.Q642X	nonsense	1	Pathogenic	0.000000
151.	c.1678delG	p.Asp560ThrfsX19	frameshift	1	Pathogenic	0.000000
152.	c.2906-2A>G		essential splice site	1	Pathogenic	0.000000
153.	c.533delT	p.Val178GlyfsX7	frameshift	1	Pathogenic	0.000000
154.	c.2524_2525insT	p.Tyr842LeufsX42	frameshift	1	Pathogenic	0.000000
155.	c.333_334insT	p.E112X	nonsense	1	Pathogenic	0.000000
156.	c.3181C>T	p.Q1061X	nonsense	1	Pathogenic	0.000016
157.	c.3373G>A	p.V1125M	missense	1	VUS favour pathogenic	0.000022
158.	c.3065G>A	p.R1022H	missense	1	VUS favour pathogenic	0.000000
159.	c.223G>A	p.D75N	missense	1	VUS favour pathogenic	0.000091
160.	c.833delG	p.Gly278GlufsX22	frameshift	1	Pathogenic	0.000000
161.	c.2610_2611insC	p.Ser871GlnfsX13	frameshift	1	Pathogenic	0.000000
162.	c.853G>A	p.D285N	missense	1	VUS	0.000000
163.	c.3694A>T	p.K1232X	nonsense	1	Pathogenic	0.000000
164.	c.3281A>T	p.N1094I	missense	1	VUS	0.000000
165.	c.2534_2538delGCGTC		frameshift	1	Pathogenic	0.000000
166.	c.3286G>T	p.E1096X	nonsense	1	Pathogenic	0.000000
167.	c.1418T>C	p.F473S	missense	1	VUS	0.000000
168.	c.1800delA		frameshift	1	Pathogenic	0.000000
169.	c.2518G>A	p.V840M	missense	1	VUS	0.000016
170.	c.3413G>C	p.R1138P	missense	1	VUS	0.000000
171.	c.1672G>A	p.A558T	missense	1	VUS	0.000008
172.	c.2312T>C	p.V771A	missense	1	VUS	0.000000
173.	c.373G>T	p.A125S	missense	1	VUS	0.000000
174.	c.3083C>G	p.T1028S	missense	1	VUS	0.000000
175.	c.3415G>A	p.V1139I	missense	1	VUS	0.000087
176.	c.2210C>T	p.T737M	missense	1	VUS	0.000050
177.	c.1000G>T	p.E334X	nonsense	1	Pathogenic	0.000000
178.	c.2723A>G	p.Y908C	missense	1	VUS	0.000062
179.	c.1090+1G>T		essential splice site	1	Pathogenic	0.000000
180.	c.1699_1700delGA	p.Glu567GlyfsX4	frameshift	1	Pathogenic	0.000000
181.	c.1456T>G	p.W486G	missense	1	Likely Pathogenic	0.000000
182.	c.1999_2000delinsG	p.Leu667AspfsX15	frameshift	1	Pathogenic	0.000000
183.	c.2394_2395insT	p.Gly799TrpfsX34	frameshift	1	Pathogenic	0.000000
184.	c.2780_2781delCA		frameshift	1	Pathogenic	0.000000
185.	c.3166_3167insG	p.Ala1056GlyfsX9	frameshift	1	Pathogenic	0.000000
186.	c.1351+1G>A		essential splice site	1	Pathogenic	0.000000
187.	c.2747G>A	p.W916X	nonsense	1	Pathogenic	0.000000
188.	c.3476_3477delTT		frameshift	1	Pathogenic	0.000000
189.	c.3797G>A	p.C1266Y	missense	1	Likely Pathogenic	0.000000
190.	c.1021G>A	p.G341S	missense	1	VUS favour pathogenic	0.000025
191.	c.821+2T>C		essential splice site	1	Pathogenic	0.000000
192.	c.3335G>A	p.W1112X	nonsense	1	Pathogenic	0.000000
193.	c.2163delC	p.Glu722ArgfsX32	frameshift	1	Pathogenic	0.000000
194.	c.3476_3479dupTTAT	p.Pro1161TyrfsX9	frameshift	1	Pathogenic	0.000000
195.	c.481C>A	p.P161T	missense	1	VUS favour pathogenic	0.000041
196.	c.2533C>T	p.R845C	missense	1	VUS favour pathogenic	0.000000
197.	c.2965G>T	p.E989X	nonsense	1	Pathogenic	0.000000
198.	c.431_432delGT	p.Gly144AlafsX8	frameshift	1	Pathogenic	0.000000
199.	c.2525A>G	p.Y842C	missense	1	VUS	0.000000
200.	c.2013_2016delinsGG	p.Pro672AspfsX20	frameshift	1	Pathogenic	0.000000
201.	c.932C>T	p.S311L	missense	1	VUS	0.000000
202.	c.566T>A	p.V189D	missense	1	VUS	0.000000
203.	c.1397T>A	p.M466K	missense	1	VUS	0.000008
204.	c.844C>T	p.R282W	missense	1	VUS favour pathogenic	0.000000
205.	c.2197C>T	p.R733C	missense	1	VUS	0.000085
206.	c.2436G>T	p.K812N	missense	1	VUS	0.000000
207.	c.2269G>A	p.V757M	missense	1	VUS	0.000066
208.	c.2828G>A	p.R943Q	missense	1	VUS	0.000025
209.	c.3811C>T	p.R1271X	nonsense	1	Pathogenic	0.000025
210.	c.655-1G>A		essential splice site	1	Pathogenic	0.000000
211.	c.104G>A	p.R35Q	missense	1	VUS	0.000079
212.	c.3825A>G	p.X1275TrpextX77	nonsense	1	Likely Pathogenic	0.000000
213.	c.2993A>G	p.Q998R	missense	1	VUS favour pathogenic	0.000000
214.	c.451G>A	p.D151N	missense	1	VUS	0.000041
215.	c.1213A>G	p.M405V	missense	1	Pathogenic	0.000000
216.	c.3776delA		frameshift	1	Pathogenic	0.000000
217.	c.1458-1G>A		essential splice site	1	Pathogenic	0.000000
218.	c.2671C>T	p.R891W	missense	1	Likely Pathogenic	0.000031
219.	c.177_187del	p.Glu60AlafsX49	frameshift	1	Pathogenic	0.000000
220.	c.3331-1G>A		essential splice site	1	Pathogenic	0.000000
221.	c.1892delT		frameshift	1	Pathogenic	0.000000
222.	c.1586C>G	p.T529S	missense	1	VUS favour pathogenic	0.000000
223.	c.3753T>G	p.Y1251X	nonsense	1	Pathogenic	0.000000
224.	c.551_552insT	p.Lys185GlufsX56	frameshift	1	Pathogenic	0.000000
225.	c.2541C>A	p.Y847X	nonsense	1	Pathogenic	0.000000
226.	c.2308+1G>T		essential splice site	1	Pathogenic	0.000000
227.	c.3548T>G	p.F1183C	missense	1	Likely Pathogenic	0.000000
228.	c.966G>A	p.W322X	nonsense	1	Pathogenic	0.000000
229.	c.1505G>T	p.R502L	missense	1	VUS favour pathogenic	0.000000
230.	c.2517_2538del	p.Val840ThrfsX32	frameshift	1	Pathogenic	0.000000
231.	c.2833_2834delCG		frameshift	1	Pathogenic	0.000000
232.	c.1168delC		frameshift	1	Pathogenic	0.000000
233.	c.713G>A	p.R238H	missense	1	VUS	0.000074
234.	c.2048G>A	p.W683X	nonsense	1	Pathogenic	0.000000
235.	c.2560A>G	p.M854V	missense	1	VUS	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.