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.355G>A	p.E119K	missense	3	VUS	0.000000
32.	c.3491-2A>T		essential splice site	3	Pathogenic	0.000000
33.	c.2873C>T	p.T958I	missense	3	VUS favour benign	0.000065
34.	c.2311_2312insG	p.Val771GlyfsX62	frameshift	3	Pathogenic	0.000000
35.	c.1591G>A	p.G531R	missense	3	VUS favour pathogenic	0.000017
36.	c.3767_3769delCCA	p.Thr1256del	inframe	3	Likely Pathogenic	0.000000
37.	c.1828G>A	p.D610N	missense	3	VUS	0.000000
38.	c.2905C>T	p.Q969X	nonsense	3	Pathogenic	0.000000
39.	c.710A>C	p.Y237S	missense	3	Likely Pathogenic	0.000000
40.	c.2450G>A	p.R817Q	missense	3	VUS favour pathogenic	0.000016
41.	c.3190+1G>A		essential splice site	3	Pathogenic	0.000000
42.	c.3233G>A	p.W1078X	nonsense	3	Pathogenic	0.000022
43.	c.2920C>T	p.Q974X	nonsense	3	Pathogenic	0.000000
44.	c.814C>T	p.R272C	missense	2	VUS	0.000083
45.	c.1934C>T	p.P645L	missense	2	VUS	0.000000
46.	c.2320G>A	p.A774T	missense	2	VUS	0.000000
47.	c.1513_1515delAAG		inframe	2	VUS favour pathogenic	0.000000
48.	c.636C>G	p.S212R	missense	2	VUS favour pathogenic	0.000000
49.	c.1897+1G>A		essential splice site	2	Pathogenic	0.000000
50.	c.1828G>C	p.D610H	missense	2	VUS favour benign	0.000058
51.	c.3627+1G>A		essential splice site	2	Pathogenic	0.000000
52.	c.1357_1358delCC		frameshift	2	Pathogenic	0.000000
53.	c.1863delC	p.Phe621LeufsX42	frameshift	2	Pathogenic	0.000000
54.	c.3192_3193insC	p.Lys1065GlnfsX12	frameshift	2	Pathogenic	0.000000
55.	c.1483C>T	p.R495W	missense	2	VUS favour pathogenic	0.000000
56.	c.1790G>A	p.R597Q	missense	2	VUS favour pathogenic	0.000000
57.	c.2943_2947delGACCA		frameshift	2	Pathogenic	0.000000
58.	c.999C>G	p.Y333X	nonsense	2	Pathogenic	0.000000
59.	c.3624_3625insC	p.Lys1209GlnfsX33	frameshift	2	Pathogenic	0.000000
60.	c.1766G>A	p.R589H	missense	2	VUS	0.000000
61.	c.927-2A>G		essential splice site	2	Pathogenic	0.000000
62.	c.2558delG		frameshift	2	Pathogenic	0.000000
63.	c.1895delT	p.Met632ArgfsX31	frameshift	2	Pathogenic	0.000000
64.	c.2882C>T	p.P961L	missense	2	VUS	0.000048
65.	c.1037G>A	p.R346H	missense	2	VUS	0.000000
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.436_437insA	p.Thr146AsnfsX7	frameshift	2	Pathogenic	0.000000
73.	c.1869C>A	p.C623X	nonsense	2	Pathogenic	0.000000
74.	c.3181C>T	p.Q1061X	nonsense	1	Pathogenic	0.000016
75.	c.2517_2538del	p.Val840ThrfsX32	frameshift	1	Pathogenic	0.000000
76.	c.223G>A	p.D75N	missense	1	VUS favour pathogenic	0.000091
77.	c.713G>A	p.R238H	missense	1	VUS	0.000074
78.	c.2560A>G	p.M854V	missense	1	VUS	0.000000
79.	c.2459G>A	p.R820Q	missense	1	Likely Pathogenic	0.000016
80.	c.3746G>T	p.G1249V	missense	1	VUS	0.000000
81.	c.2905+1G>C		essential splice site	1	Pathogenic	0.000000
82.	c.3098G>A	p.R1033Q	missense	1	VUS	0.000000
83.	c.1800delA		frameshift	1	Pathogenic	0.000000
84.	c.1351+2T>C		essential splice site	1	Pathogenic	0.000000
85.	c.1273C>T	p.Q425X	nonsense	1	Pathogenic	0.000000
86.	c.3068_3069insA	p.Asn1023LysfsX28	frameshift	1	Pathogenic	0.000000
87.	c.2113_2114insA	p.Thr705AsnfsX3	frameshift	1	Pathogenic	0.000000
88.	c.3690_3691delCA	p.Phe1230LeufsX11	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.3253G>T	p.E1085X	nonsense	1	Pathogenic	0.000000
92.	c.1456T>G	p.W486G	missense	1	Likely Pathogenic	0.000000
93.	c.2875_2876delAC	p.Thr959GlyfsX91	frameshift	1	Pathogenic	0.000000
94.	c.2780_2781delCA		frameshift	1	Pathogenic	0.000000
95.	c.993_994insT	p.E332X	nonsense	1	Pathogenic	0.000000
96.	c.2528_2536delAGATGCGCG	p.Glu843_Arg845del	inframe	1	Pathogenic	0.000000
97.	c.1351+1G>A		essential splice site	1	Pathogenic	0.000000
98.	c.3476_3477delTT		frameshift	1	Pathogenic	0.000000
99.	c.290C>T	p.A97V	missense	1	VUS favour pathogenic	0.000000
100.	c.3797G>A	p.C1266Y	missense	1	Likely Pathogenic	0.000000
101.	c.2040_2041insT	p.Val681CysfsX12	frameshift	1	Pathogenic	0.000000
102.	c.3580G>A	p.A1194T	missense	1	VUS	0.000008
103.	c.1188G>T	p.W396C	missense	1	VUS	0.000000
104.	c.3335G>A	p.W1112X	nonsense	1	Pathogenic	0.000000
105.	c.436A>C	p.T146P	missense	1	VUS	0.000000
106.	c.481C>A	p.P161T	missense	1	VUS favour pathogenic	0.000041
107.	c.506-1G>T		essential splice site	1	Pathogenic	0.000000
108.	c.2234A>G	p.D745G	missense	1	VUS	0.000000
109.	c.326C>T	p.A109V	missense	1	VUS	0.000000
110.	c.1021G>A	p.G341S	missense	1	VUS favour pathogenic	0.000025
111.	c.931T>A	p.S311T	missense	1	VUS	0.000000
112.	c.1540A>G	p.I514V	missense	1	VUS	0.000008
113.	c.3049G>A	p.E1017K	missense	1	VUS favour benign	0.000085
114.	c.2938C>T	p.R980C	missense	1	VUS	0.000062
115.	c.2308+1G>A		essential splice site	1	Pathogenic	0.000000
116.	c.2170C>T	p.R724W	missense	1	VUS	0.000019
117.	c.3676C>T	p.R1226C	missense	1	VUS	0.000058
118.	c.1358C>T	p.P453L	missense	1	VUS	0.000008
119.	c.1294G>A	p.A432T	missense	1	VUS	0.000037
120.	c.3G>C	p.Met1?	missense	1	Likely Pathogenic	0.000000
121.	c.2557G>A	p.G853S	missense	1	VUS	0.000008
122.	c.655-1G>A		essential splice site	1	Pathogenic	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.3040delC	p.Leu1014TrpfsX6	frameshift	1	Pathogenic	0.000000
128.	c.1213A>G	p.M405V	missense	1	Pathogenic	0.000000
129.	c.3332_3335dupAGTG	p.W1112X	nonsense	1	Pathogenic	0.000000
130.	c.1841A>G	p.Y614C	missense	1	VUS favour pathogenic	0.000000
131.	c.2671C>T	p.R891W	missense	1	Likely Pathogenic	0.000031
132.	c.2953A>T	p.K985X	nonsense	1	Pathogenic	0.000000
133.	c.613C>T	p.Q205X	nonsense	1	Pathogenic	0.000000
134.	c.3776delA		frameshift	1	Pathogenic	0.000000
135.	c.3815-1G>A		essential splice site	1	Pathogenic	0.000000
136.	c.1892delT		frameshift	1	Pathogenic	0.000000
137.	c.2449C>T	p.R817W	missense	1	VUS	0.000000
138.	c.3753T>G	p.Y1251X	nonsense	1	Pathogenic	0.000000
139.	c.2641G>A	p.V881I	missense	1	VUS	0.000018
140.	c.2939G>A	p.R980H	missense	1	VUS	0.000000
141.	c.1535T>A	p.L512Q	missense	1	VUS favour pathogenic	0.000000
142.	c.3742G>A	p.G1248R	missense	1	VUS	0.000033
143.	c.518C>A	p.T173N	missense	1	VUS	0.000000
144.	c.1950C>G	p.D650E	missense	1	VUS	0.000000
145.	c.3373G>A	p.V1125M	missense	1	VUS favour pathogenic	0.000022
146.	c.103C>T	p.R35W	missense	1	VUS	0.000056
147.	c.2654C>T	p.T885M	missense	1	VUS	0.000022
148.	c.2048G>A	p.W683X	nonsense	1	Pathogenic	0.000000
149.	c.2534_2538delGCGTC		frameshift	1	Pathogenic	0.000000
150.	c.3286G>T	p.E1096X	nonsense	1	Pathogenic	0.000000
151.	c.3791G>A	p.C1264Y	missense	1	VUS	0.000008
152.	c.2737+1G>C		essential splice site	1	Pathogenic	0.000000
153.	c.3277G>T	p.G1093C	missense	1	VUS	0.000020
154.	c.2149-1G>A		essential splice site	1	Pathogenic	0.000000
155.	c.821+1G>C		essential splice site	1	Pathogenic	0.000000
156.	c.3288delG		frameshift	1	Pathogenic	0.000000
157.	c.1678delG	p.Asp560ThrfsX19	frameshift	1	Pathogenic	0.000000
158.	c.2556_2557delinsTCT	p.Gly853fs	frameshift	1	Pathogenic	0.000000
159.	c.533delT	p.Val178GlyfsX7	frameshift	1	Pathogenic	0.000000
160.	c.2524_2525insT	p.Tyr842LeufsX42	frameshift	1	Pathogenic	0.000000
161.	c.1156G>T	p.E386X	nonsense	1	Pathogenic	0.000000
162.	c.333_334insT	p.E112X	nonsense	1	Pathogenic	0.000000
163.	c.2906-2A>G		essential splice site	1	Pathogenic	0.000000
164.	c.3065G>A	p.R1022H	missense	1	VUS favour pathogenic	0.000000
165.	c.1090+1G>A		essential splice site	1	Pathogenic	0.000000
166.	c.833delG	p.Gly278GlufsX22	frameshift	1	Pathogenic	0.000000
167.	c.2610_2611insC	p.Ser871GlnfsX13	frameshift	1	Pathogenic	0.000000
168.	c.1628delA		frameshift	1	Pathogenic	0.000000
169.	c.3281A>T	p.N1094I	missense	1	VUS	0.000000
170.	c.1778C>T	p.S593F	missense	1	VUS favour pathogenic	0.000034
171.	c.1418T>C	p.F473S	missense	1	VUS	0.000000
172.	c.853G>A	p.D285N	missense	1	VUS	0.000000
173.	c.3694A>T	p.K1232X	nonsense	1	Pathogenic	0.000000
174.	c.2518G>A	p.V840M	missense	1	VUS	0.000016
175.	c.3413G>C	p.R1138P	missense	1	VUS	0.000000
176.	c.1672G>A	p.A558T	missense	1	VUS	0.000008
177.	c.2312T>C	p.V771A	missense	1	VUS	0.000000
178.	c.373G>T	p.A125S	missense	1	VUS	0.000000
179.	c.3083C>G	p.T1028S	missense	1	VUS	0.000000
180.	c.3415G>A	p.V1139I	missense	1	VUS	0.000087
181.	c.2210C>T	p.T737M	missense	1	VUS	0.000050
182.	c.3065G>C	p.R1022P	missense	1	VUS favour pathogenic	0.000025
183.	c.1000G>T	p.E334X	nonsense	1	Pathogenic	0.000000
184.	c.844C>T	p.R282W	missense	1	VUS favour pathogenic	0.000000
185.	c.2723A>G	p.Y908C	missense	1	VUS	0.000062
186.	c.1699_1700delGA	p.Glu567GlyfsX4	frameshift	1	Pathogenic	0.000000
187.	c.1999_2000delinsG	p.Leu667AspfsX15	frameshift	1	Pathogenic	0.000000
188.	c.1693A>T	p.K565X	nonsense	1	Pathogenic	0.000000
189.	c.3166_3167insG	p.Ala1056GlyfsX9	frameshift	1	Pathogenic	0.000000
190.	c.1591G>C	p.G531R	missense	1	VUS favour pathogenic	0.000017
191.	c.1575T>G	p.Y525X	nonsense	1	Pathogenic	0.000000
192.	c.2747G>A	p.W916X	nonsense	1	Pathogenic	0.000000
193.	c.1038_1042dupCGGCA		frameshift	1	Pathogenic	0.000008
194.	c.2394_2395insT	p.Gly799TrpfsX34	frameshift	1	Pathogenic	0.000000
195.	c.2163delC	p.Glu722ArgfsX32	frameshift	1	Pathogenic	0.000000
196.	c.1224-2A>G		essential splice site	1	Pathogenic	0.000000
197.	c.3476_3479dupTTAT	p.Pro1161TyrfsX9	frameshift	1	Pathogenic	0.000000
198.	c.3408C>A	p.Y1136X	nonsense	1	Pathogenic	0.000000
199.	c.2533C>T	p.R845C	missense	1	VUS favour pathogenic	0.000000
200.	c.3735delC		frameshift	1	Likely Pathogenic	0.000000
201.	c.2965G>T	p.E989X	nonsense	1	Pathogenic	0.000000
202.	c.2490_2491insT	p.His831SerfsTer2	frameshift	1	Pathogenic	0.000024
203.	c.821+2T>C		essential splice site	1	Pathogenic	0.000000
204.	c.3763G>A	p.A1255T	missense	1	VUS favour pathogenic	0.000075
205.	c.431_432delGT	p.Gly144AlafsX8	frameshift	1	Pathogenic	0.000000
206.	c.2525A>G	p.Y842C	missense	1	VUS	0.000000
207.	c.459delC		frameshift	1	Pathogenic	0.000000
208.	c.2013_2016delinsGG	p.Pro672AspfsX20	frameshift	1	Pathogenic	0.000000
209.	c.1397T>A	p.M466K	missense	1	VUS	0.000008
210.	c.2197C>T	p.R733C	missense	1	VUS	0.000085
211.	c.2436G>T	p.K812N	missense	1	VUS	0.000000
212.	c.2269G>A	p.V757M	missense	1	VUS	0.000066
213.	c.1960C>T	p.R654C	missense	1	VUS favour benign	0.000008
214.	c.932C>T	p.S311L	missense	1	VUS	0.000000
215.	c.566T>A	p.V189D	missense	1	VUS	0.000000
216.	c.2308+1G>T		essential splice site	1	Pathogenic	0.000000
217.	c.2828G>A	p.R943Q	missense	1	VUS	0.000025
218.	c.1624+2T>C		essential splice site	1	Pathogenic	0.000000
219.	c.104G>A	p.R35Q	missense	1	VUS	0.000079
220.	c.2833_2834delCG		frameshift	1	Pathogenic	0.000000
221.	c.3825A>G	p.X1275TrpextX77	nonsense	1	Likely Pathogenic	0.000000
222.	c.1168delC		frameshift	1	Pathogenic	0.000000
223.	c.451G>A	p.D151N	missense	1	VUS	0.000041
224.	c.1458-1G>A		essential splice site	1	Pathogenic	0.000000
225.	c.177_187del	p.Glu60AlafsX49	frameshift	1	Pathogenic	0.000000
226.	c.1586C>G	p.T529S	missense	1	VUS favour pathogenic	0.000000
227.	c.1343T>C	p.F448S	missense	1	Likely Pathogenic	0.000000
228.	c.1924C>T	p.Q642X	nonsense	1	Pathogenic	0.000000
229.	c.551_552insT	p.Lys185GlufsX56	frameshift	1	Pathogenic	0.000000
230.	c.2541C>A	p.Y847X	nonsense	1	Pathogenic	0.000000
231.	c.3331-1G>A		essential splice site	1	Pathogenic	0.000000
232.	c.932C>A	p.S311X	nonsense	1	Pathogenic	0.000000
233.	c.3548T>G	p.F1183C	missense	1	Likely Pathogenic	0.000000
234.	c.966G>A	p.W322X	nonsense	1	Pathogenic	0.000000
235.	c.1505G>T	p.R502L	missense	1	VUS favour 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.