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.2827C>T	p.R943X	nonsense	7	Pathogenic	0.000017
13.	c.2670G>A	p.W890X	nonsense	7	Pathogenic	0.000000
14.	c.442G>A	p.G148R	missense	7	VUS favour pathogenic	0.000042
15.	c.2864_2865delCT		frameshift	6	Pathogenic	0.000000
16.	c.2308G>A	p.D770N	missense	6	Likely Pathogenic	0.000008
17.	c.3226_3227insT		frameshift	6	Pathogenic	0.000000
18.	c.1505G>A	p.R502Q	missense	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.2573G>A	p.S858N	missense	4	VUS favour pathogenic	0.000000
22.	c.2096delC		frameshift	4	Pathogenic	0.000000
23.	c.26-2A>G		essential splice site	4	Pathogenic	0.000051
24.	c.821+1G>A		essential splice site	4	Pathogenic	0.000043
25.	c.1483C>G	p.R495G	missense	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.2182G>T	p.E728X	nonsense	4	Pathogenic	0.000000
30.	c.3742_3759dup	p.Gly1248_Cys1253dup	inframe	4	Likely Pathogenic	0.000000
31.	c.1828G>A	p.D610N	missense	3	VUS	0.000000
32.	c.355G>A	p.E119K	missense	3	VUS	0.000000
33.	c.3190+1G>A		essential splice site	3	Pathogenic	0.000000
34.	c.2873C>T	p.T958I	missense	3	VUS favour benign	0.000065
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.2920C>T	p.Q974X	nonsense	3	Pathogenic	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.3491-2A>T		essential splice site	3	Pathogenic	0.000000
42.	c.3233G>A	p.W1078X	nonsense	3	Pathogenic	0.000022
43.	c.2311_2312insG	p.Val771GlyfsX62	frameshift	3	Pathogenic	0.000000
44.	c.1210C>T	p.Q404X	nonsense	2	Pathogenic	0.000000
45.	c.532G>A	p.V178M	missense	2	VUS favour pathogenic	0.000020
46.	c.1869C>A	p.C623X	nonsense	2	Pathogenic	0.000000
47.	c.436_437insA	p.Thr146AsnfsX7	frameshift	2	Pathogenic	0.000000
48.	c.3624delC		frameshift	2	Pathogenic	0.000000
49.	c.3190+2T>G		essential splice site	2	Pathogenic	0.000016
50.	c.1934C>T	p.P645L	missense	2	VUS	0.000000
51.	c.3192_3193insC	p.Lys1065GlnfsX12	frameshift	2	Pathogenic	0.000000
52.	c.3624_3625insC	p.Lys1209GlnfsX33	frameshift	2	Pathogenic	0.000000
53.	c.999C>G	p.Y333X	nonsense	2	Pathogenic	0.000000
54.	c.1766G>A	p.R589H	missense	2	VUS	0.000000
55.	c.1513_1515delAAG		inframe	2	VUS favour pathogenic	0.000000
56.	c.636C>G	p.S212R	missense	2	VUS favour pathogenic	0.000000
57.	c.1895delT	p.Met632ArgfsX31	frameshift	2	Pathogenic	0.000000
58.	c.3627+1G>A		essential splice site	2	Pathogenic	0.000000
59.	c.1357_1358delCC		frameshift	2	Pathogenic	0.000000
60.	c.772+1G>A		essential splice site	2	Pathogenic	0.000000
61.	c.2604_2605delinsA	p.S871fs	frameshift	2	Pathogenic	0.000000
62.	c.814C>T	p.R272C	missense	2	VUS	0.000083
63.	c.1790G>A	p.R597Q	missense	2	VUS favour pathogenic	0.000000
64.	c.1483C>T	p.R495W	missense	2	VUS favour pathogenic	0.000000
65.	c.2320G>A	p.A774T	missense	2	VUS	0.000000
66.	c.2943_2947delGACCA		frameshift	2	Pathogenic	0.000000
67.	c.1897+1G>A		essential splice site	2	Pathogenic	0.000000
68.	c.927-2A>G		essential splice site	2	Pathogenic	0.000000
69.	c.2558delG		frameshift	2	Pathogenic	0.000000
70.	c.1828G>C	p.D610H	missense	2	VUS favour benign	0.000058
71.	c.2882C>T	p.P961L	missense	2	VUS	0.000048
72.	c.1037G>A	p.R346H	missense	2	VUS	0.000000
73.	c.1863delC	p.Phe621LeufsX42	frameshift	2	Pathogenic	0.000000
74.	c.1535T>A	p.L512Q	missense	1	VUS favour pathogenic	0.000000
75.	c.1624+2T>C		essential splice site	1	Pathogenic	0.000000
76.	c.1168delC		frameshift	1	Pathogenic	0.000000
77.	c.3742G>A	p.G1248R	missense	1	VUS	0.000033
78.	c.2654C>T	p.T885M	missense	1	VUS	0.000022
79.	c.932C>A	p.S311X	nonsense	1	Pathogenic	0.000000
80.	c.3373G>A	p.V1125M	missense	1	VUS favour pathogenic	0.000022
81.	c.1343T>C	p.F448S	missense	1	Likely Pathogenic	0.000000
82.	c.1586C>G	p.T529S	missense	1	VUS favour pathogenic	0.000000
83.	c.103C>T	p.R35W	missense	1	VUS	0.000056
84.	c.1924C>T	p.Q642X	nonsense	1	Pathogenic	0.000000
85.	c.2737+1G>C		essential splice site	1	Pathogenic	0.000000
86.	c.3277G>T	p.G1093C	missense	1	VUS	0.000020
87.	c.2534_2538delGCGTC		frameshift	1	Pathogenic	0.000000
88.	c.3548T>G	p.F1183C	missense	1	Likely Pathogenic	0.000000
89.	c.3791G>A	p.C1264Y	missense	1	VUS	0.000008
90.	c.966G>A	p.W322X	nonsense	1	Pathogenic	0.000000
91.	c.2556_2557delinsTCT	p.Gly853fs	frameshift	1	Pathogenic	0.000000
92.	c.3181C>T	p.Q1061X	nonsense	1	Pathogenic	0.000016
93.	c.2517_2538del	p.Val840ThrfsX32	frameshift	1	Pathogenic	0.000000
94.	c.2149-1G>A		essential splice site	1	Pathogenic	0.000000
95.	c.821+1G>C		essential splice site	1	Pathogenic	0.000000
96.	c.223G>A	p.D75N	missense	1	VUS favour pathogenic	0.000091
97.	c.1678delG	p.Asp560ThrfsX19	frameshift	1	Pathogenic	0.000000
98.	c.2906-2A>G		essential splice site	1	Pathogenic	0.000000
99.	c.533delT	p.Val178GlyfsX7	frameshift	1	Pathogenic	0.000000
100.	c.2524_2525insT	p.Tyr842LeufsX42	frameshift	1	Pathogenic	0.000000
101.	c.333_334insT	p.E112X	nonsense	1	Pathogenic	0.000000
102.	c.1800delA		frameshift	1	Pathogenic	0.000000
103.	c.1273C>T	p.Q425X	nonsense	1	Pathogenic	0.000000
104.	c.1456T>G	p.W486G	missense	1	Likely Pathogenic	0.000000
105.	c.2518G>A	p.V840M	missense	1	VUS	0.000016
106.	c.1090+1G>T		essential splice site	1	Pathogenic	0.000000
107.	c.1672G>A	p.A558T	missense	1	VUS	0.000008
108.	c.2210C>T	p.T737M	missense	1	VUS	0.000050
109.	c.3476_3477delTT		frameshift	1	Pathogenic	0.000000
110.	c.3797G>A	p.C1266Y	missense	1	Likely Pathogenic	0.000000
111.	c.290C>T	p.A97V	missense	1	VUS favour pathogenic	0.000000
112.	c.373G>T	p.A125S	missense	1	VUS	0.000000
113.	c.2780_2781delCA		frameshift	1	Pathogenic	0.000000
114.	c.3083C>G	p.T1028S	missense	1	VUS	0.000000
115.	c.1351+1G>A		essential splice site	1	Pathogenic	0.000000
116.	c.2528_2536delAGATGCGCG	p.Glu843_Arg845del	inframe	1	Pathogenic	0.000000
117.	c.3415G>A	p.V1139I	missense	1	VUS	0.000087
118.	c.506-1G>T		essential splice site	1	Pathogenic	0.000000
119.	c.1999_2000delinsG	p.Leu667AspfsX15	frameshift	1	Pathogenic	0.000000
120.	c.1021G>A	p.G341S	missense	1	VUS favour pathogenic	0.000025
121.	c.326C>T	p.A109V	missense	1	VUS	0.000000
122.	c.2040_2041insT	p.Val681CysfsX12	frameshift	1	Pathogenic	0.000000
123.	c.1000G>T	p.E334X	nonsense	1	Pathogenic	0.000000
124.	c.2723A>G	p.Y908C	missense	1	VUS	0.000062
125.	c.3580G>A	p.A1194T	missense	1	VUS	0.000008
126.	c.3335G>A	p.W1112X	nonsense	1	Pathogenic	0.000000
127.	c.1188G>T	p.W396C	missense	1	VUS	0.000000
128.	c.1699_1700delGA	p.Glu567GlyfsX4	frameshift	1	Pathogenic	0.000000
129.	c.481C>A	p.P161T	missense	1	VUS favour pathogenic	0.000041
130.	c.436A>C	p.T146P	missense	1	VUS	0.000000
131.	c.2394_2395insT	p.Gly799TrpfsX34	frameshift	1	Pathogenic	0.000000
132.	c.931T>A	p.S311T	missense	1	VUS	0.000000
133.	c.3166_3167insG	p.Ala1056GlyfsX9	frameshift	1	Pathogenic	0.000000
134.	c.2747G>A	p.W916X	nonsense	1	Pathogenic	0.000000
135.	c.2965G>T	p.E989X	nonsense	1	Pathogenic	0.000000
136.	c.821+2T>C		essential splice site	1	Pathogenic	0.000000
137.	c.3476_3479dupTTAT	p.Pro1161TyrfsX9	frameshift	1	Pathogenic	0.000000
138.	c.932C>T	p.S311L	missense	1	VUS	0.000000
139.	c.1397T>A	p.M466K	missense	1	VUS	0.000008
140.	c.655-1G>A		essential splice site	1	Pathogenic	0.000000
141.	c.2993A>G	p.Q998R	missense	1	VUS favour pathogenic	0.000000
142.	c.2269G>A	p.V757M	missense	1	VUS	0.000066
143.	c.3811C>T	p.R1271X	nonsense	1	Pathogenic	0.000025
144.	c.3776delA		frameshift	1	Pathogenic	0.000000
145.	c.2828G>A	p.R943Q	missense	1	VUS	0.000025
146.	c.1213A>G	p.M405V	missense	1	Pathogenic	0.000000
147.	c.2671C>T	p.R891W	missense	1	Likely Pathogenic	0.000031
148.	c.1841A>G	p.Y614C	missense	1	VUS favour pathogenic	0.000000
149.	c.451G>A	p.D151N	missense	1	VUS	0.000041
150.	c.2641G>A	p.V881I	missense	1	VUS	0.000018
151.	c.2939G>A	p.R980H	missense	1	VUS	0.000000
152.	c.1892delT		frameshift	1	Pathogenic	0.000000
153.	c.3815-1G>A		essential splice site	1	Pathogenic	0.000000
154.	c.2833_2834delCG		frameshift	1	Pathogenic	0.000000
155.	c.104G>A	p.R35Q	missense	1	VUS	0.000079
156.	c.3753T>G	p.Y1251X	nonsense	1	Pathogenic	0.000000
157.	c.2449C>T	p.R817W	missense	1	VUS	0.000000
158.	c.3825A>G	p.X1275TrpextX77	nonsense	1	Likely Pathogenic	0.000000
159.	c.518C>A	p.T173N	missense	1	VUS	0.000000
160.	c.177_187del	p.Glu60AlafsX49	frameshift	1	Pathogenic	0.000000
161.	c.1950C>G	p.D650E	missense	1	VUS	0.000000
162.	c.1458-1G>A		essential splice site	1	Pathogenic	0.000000
163.	c.3331-1G>A		essential splice site	1	Pathogenic	0.000000
164.	c.551_552insT	p.Lys185GlufsX56	frameshift	1	Pathogenic	0.000000
165.	c.2541C>A	p.Y847X	nonsense	1	Pathogenic	0.000000
166.	c.1505G>T	p.R502L	missense	1	VUS favour pathogenic	0.000000
167.	c.2048G>A	p.W683X	nonsense	1	Pathogenic	0.000000
168.	c.3286G>T	p.E1096X	nonsense	1	Pathogenic	0.000000
169.	c.3288delG		frameshift	1	Pathogenic	0.000000
170.	c.2459G>A	p.R820Q	missense	1	Likely Pathogenic	0.000016
171.	c.713G>A	p.R238H	missense	1	VUS	0.000074
172.	c.2560A>G	p.M854V	missense	1	VUS	0.000000
173.	c.1156G>T	p.E386X	nonsense	1	Pathogenic	0.000000
174.	c.1628delA		frameshift	1	Pathogenic	0.000000
175.	c.2610_2611insC	p.Ser871GlnfsX13	frameshift	1	Pathogenic	0.000000
176.	c.1090+1G>A		essential splice site	1	Pathogenic	0.000000
177.	c.3065G>A	p.R1022H	missense	1	VUS favour pathogenic	0.000000
178.	c.3746G>T	p.G1249V	missense	1	VUS	0.000000
179.	c.833delG	p.Gly278GlufsX22	frameshift	1	Pathogenic	0.000000
180.	c.2905+1G>C		essential splice site	1	Pathogenic	0.000000
181.	c.3098G>A	p.R1033Q	missense	1	VUS	0.000000
182.	c.3068_3069insA	p.Asn1023LysfsX28	frameshift	1	Pathogenic	0.000000
183.	c.853G>A	p.D285N	missense	1	VUS	0.000000
184.	c.3694A>T	p.K1232X	nonsense	1	Pathogenic	0.000000
185.	c.2113_2114insA	p.Thr705AsnfsX3	frameshift	1	Pathogenic	0.000000
186.	c.1778C>T	p.S593F	missense	1	VUS favour pathogenic	0.000034
187.	c.3281A>T	p.N1094I	missense	1	VUS	0.000000
188.	c.1351+2T>C		essential splice site	1	Pathogenic	0.000000
189.	c.1418T>C	p.F473S	missense	1	VUS	0.000000
190.	c.2875_2876delAC	p.Thr959GlyfsX91	frameshift	1	Pathogenic	0.000000
191.	c.3690_3691delCA	p.Phe1230LeufsX11	frameshift	1	Pathogenic	0.000000
192.	c.2437A>T	p.K813X	nonsense	1	Pathogenic	0.000000
193.	c.3413G>C	p.R1138P	missense	1	VUS	0.000000
194.	c.3253G>T	p.E1085X	nonsense	1	Pathogenic	0.000000
195.	c.2312T>C	p.V771A	missense	1	VUS	0.000000
196.	c.993_994insT	p.E332X	nonsense	1	Pathogenic	0.000000
197.	c.1693A>T	p.K565X	nonsense	1	Pathogenic	0.000000
198.	c.2234A>G	p.D745G	missense	1	VUS	0.000000
199.	c.3065G>C	p.R1022P	missense	1	VUS favour pathogenic	0.000025
200.	c.844C>T	p.R282W	missense	1	VUS favour pathogenic	0.000000
201.	c.1591G>C	p.G531R	missense	1	VUS favour pathogenic	0.000017
202.	c.1540A>G	p.I514V	missense	1	VUS	0.000008
203.	c.1575T>G	p.Y525X	nonsense	1	Pathogenic	0.000000
204.	c.1038_1042dupCGGCA		frameshift	1	Pathogenic	0.000008
205.	c.2533C>T	p.R845C	missense	1	VUS favour pathogenic	0.000000
206.	c.3676C>T	p.R1226C	missense	1	VUS	0.000058
207.	c.1358C>T	p.P453L	missense	1	VUS	0.000008
208.	c.2490_2491insT	p.His831SerfsTer2	frameshift	1	Pathogenic	0.000024
209.	c.3049G>A	p.E1017K	missense	1	VUS favour benign	0.000085
210.	c.1224-2A>G		essential splice site	1	Pathogenic	0.000000
211.	c.2163delC	p.Glu722ArgfsX32	frameshift	1	Pathogenic	0.000000
212.	c.2308+1G>A		essential splice site	1	Pathogenic	0.000000
213.	c.2938C>T	p.R980C	missense	1	VUS	0.000062
214.	c.2170C>T	p.R724W	missense	1	VUS	0.000019
215.	c.3408C>A	p.Y1136X	nonsense	1	Pathogenic	0.000000
216.	c.3735delC		frameshift	1	Likely Pathogenic	0.000000
217.	c.459delC		frameshift	1	Pathogenic	0.000000
218.	c.2525A>G	p.Y842C	missense	1	VUS	0.000000
219.	c.2013_2016delinsGG	p.Pro672AspfsX20	frameshift	1	Pathogenic	0.000000
220.	c.3G>C	p.Met1?	missense	1	Likely Pathogenic	0.000000
221.	c.2557G>A	p.G853S	missense	1	VUS	0.000008
222.	c.3763G>A	p.A1255T	missense	1	VUS favour pathogenic	0.000075
223.	c.431_432delGT	p.Gly144AlafsX8	frameshift	1	Pathogenic	0.000000
224.	c.1294G>A	p.A432T	missense	1	VUS	0.000037
225.	c.566T>A	p.V189D	missense	1	VUS	0.000000
226.	c.3040delC	p.Leu1014TrpfsX6	frameshift	1	Pathogenic	0.000000
227.	c.2197C>T	p.R733C	missense	1	VUS	0.000085
228.	c.2436G>T	p.K812N	missense	1	VUS	0.000000
229.	c.2737+2T>A		essential splice site	1	Pathogenic	0.000000
230.	c.3605G>A	p.C1202Y	missense	1	Likely Pathogenic	0.000000
231.	c.1960C>T	p.R654C	missense	1	VUS favour benign	0.000008
232.	c.613C>T	p.Q205X	nonsense	1	Pathogenic	0.000000
233.	c.2308+1G>T		essential splice site	1	Pathogenic	0.000000
234.	c.3332_3335dupAGTG	p.W1112X	nonsense	1	Pathogenic	0.000000
235.	c.2953A>T	p.K985X	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.