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.442G>A	p.G148R	missense	7	VUS favour pathogenic	0.000042
13.	c.2827C>T	p.R943X	nonsense	7	Pathogenic	0.000017
14.	c.2670G>A	p.W890X	nonsense	7	Pathogenic	0.000000
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.913_914delTT		frameshift	5	Pathogenic	0.000000
20.	c.2374T>C	p.W792R	missense	5	Likely Pathogenic	0.000000
21.	c.3742_3759dup	p.Gly1248_Cys1253dup	inframe	4	Likely Pathogenic	0.000000
22.	c.2573G>A	p.S858N	missense	4	VUS favour pathogenic	0.000000
23.	c.2096delC		frameshift	4	Pathogenic	0.000000
24.	c.26-2A>G		essential splice site	4	Pathogenic	0.000051
25.	c.821+1G>A		essential splice site	4	Pathogenic	0.000043
26.	c.1483C>G	p.R495G	missense	4	Likely Pathogenic	0.000000
27.	c.2905+1G>A		essential splice site	4	Pathogenic	0.000000
28.	c.2454G>A	p.W818X	nonsense	4	Pathogenic	0.000000
29.	c.3064C>T	p.R1022C	missense	4	VUS favour pathogenic	0.000008
30.	c.2182G>T	p.E728X	nonsense	4	Pathogenic	0.000000
31.	c.3233G>A	p.W1078X	nonsense	3	Pathogenic	0.000022
32.	c.2311_2312insG	p.Val771GlyfsX62	frameshift	3	Pathogenic	0.000000
33.	c.1828G>A	p.D610N	missense	3	VUS	0.000000
34.	c.355G>A	p.E119K	missense	3	VUS	0.000000
35.	c.3190+1G>A		essential splice site	3	Pathogenic	0.000000
36.	c.2873C>T	p.T958I	missense	3	VUS favour benign	0.000065
37.	c.1591G>A	p.G531R	missense	3	VUS favour pathogenic	0.000017
38.	c.3767_3769delCCA	p.Thr1256del	inframe	3	Likely Pathogenic	0.000000
39.	c.2905C>T	p.Q969X	nonsense	3	Pathogenic	0.000000
40.	c.2920C>T	p.Q974X	nonsense	3	Pathogenic	0.000000
41.	c.710A>C	p.Y237S	missense	3	Likely Pathogenic	0.000000
42.	c.2450G>A	p.R817Q	missense	3	VUS favour pathogenic	0.000016
43.	c.3491-2A>T		essential splice site	3	Pathogenic	0.000000
44.	c.2558delG		frameshift	2	Pathogenic	0.000000
45.	c.1828G>C	p.D610H	missense	2	VUS favour benign	0.000058
46.	c.2882C>T	p.P961L	missense	2	VUS	0.000048
47.	c.1037G>A	p.R346H	missense	2	VUS	0.000000
48.	c.1863delC	p.Phe621LeufsX42	frameshift	2	Pathogenic	0.000000
49.	c.532G>A	p.V178M	missense	2	VUS favour pathogenic	0.000020
50.	c.1210C>T	p.Q404X	nonsense	2	Pathogenic	0.000000
51.	c.3190+2T>G		essential splice site	2	Pathogenic	0.000016
52.	c.1869C>A	p.C623X	nonsense	2	Pathogenic	0.000000
53.	c.436_437insA	p.Thr146AsnfsX7	frameshift	2	Pathogenic	0.000000
54.	c.3624delC		frameshift	2	Pathogenic	0.000000
55.	c.1934C>T	p.P645L	missense	2	VUS	0.000000
56.	c.3192_3193insC	p.Lys1065GlnfsX12	frameshift	2	Pathogenic	0.000000
57.	c.999C>G	p.Y333X	nonsense	2	Pathogenic	0.000000
58.	c.3624_3625insC	p.Lys1209GlnfsX33	frameshift	2	Pathogenic	0.000000
59.	c.1766G>A	p.R589H	missense	2	VUS	0.000000
60.	c.1513_1515delAAG		inframe	2	VUS favour pathogenic	0.000000
61.	c.636C>G	p.S212R	missense	2	VUS favour pathogenic	0.000000
62.	c.1895delT	p.Met632ArgfsX31	frameshift	2	Pathogenic	0.000000
63.	c.1357_1358delCC		frameshift	2	Pathogenic	0.000000
64.	c.3627+1G>A		essential splice site	2	Pathogenic	0.000000
65.	c.772+1G>A		essential splice site	2	Pathogenic	0.000000
66.	c.2604_2605delinsA	p.S871fs	frameshift	2	Pathogenic	0.000000
67.	c.814C>T	p.R272C	missense	2	VUS	0.000083
68.	c.1790G>A	p.R597Q	missense	2	VUS favour pathogenic	0.000000
69.	c.1483C>T	p.R495W	missense	2	VUS favour pathogenic	0.000000
70.	c.2943_2947delGACCA		frameshift	2	Pathogenic	0.000000
71.	c.2320G>A	p.A774T	missense	2	VUS	0.000000
72.	c.1897+1G>A		essential splice site	2	Pathogenic	0.000000
73.	c.927-2A>G		essential splice site	2	Pathogenic	0.000000
74.	c.1693A>T	p.K565X	nonsense	1	Pathogenic	0.000000
75.	c.2234A>G	p.D745G	missense	1	VUS	0.000000
76.	c.3065G>C	p.R1022P	missense	1	VUS favour pathogenic	0.000025
77.	c.844C>T	p.R282W	missense	1	VUS favour pathogenic	0.000000
78.	c.1540A>G	p.I514V	missense	1	VUS	0.000008
79.	c.1575T>G	p.Y525X	nonsense	1	Pathogenic	0.000000
80.	c.1038_1042dupCGGCA		frameshift	1	Pathogenic	0.000008
81.	c.1591G>C	p.G531R	missense	1	VUS favour pathogenic	0.000017
82.	c.2308+1G>A		essential splice site	1	Pathogenic	0.000000
83.	c.2938C>T	p.R980C	missense	1	VUS	0.000062
84.	c.2170C>T	p.R724W	missense	1	VUS	0.000019
85.	c.3408C>A	p.Y1136X	nonsense	1	Pathogenic	0.000000
86.	c.3735delC		frameshift	1	Likely Pathogenic	0.000000
87.	c.2533C>T	p.R845C	missense	1	VUS favour pathogenic	0.000000
88.	c.3676C>T	p.R1226C	missense	1	VUS	0.000058
89.	c.1358C>T	p.P453L	missense	1	VUS	0.000008
90.	c.2490_2491insT	p.His831SerfsTer2	frameshift	1	Pathogenic	0.000024
91.	c.3049G>A	p.E1017K	missense	1	VUS favour benign	0.000085
92.	c.1224-2A>G		essential splice site	1	Pathogenic	0.000000
93.	c.2163delC	p.Glu722ArgfsX32	frameshift	1	Pathogenic	0.000000
94.	c.431_432delGT	p.Gly144AlafsX8	frameshift	1	Pathogenic	0.000000
95.	c.1294G>A	p.A432T	missense	1	VUS	0.000037
96.	c.459delC		frameshift	1	Pathogenic	0.000000
97.	c.2525A>G	p.Y842C	missense	1	VUS	0.000000
98.	c.2013_2016delinsGG	p.Pro672AspfsX20	frameshift	1	Pathogenic	0.000000
99.	c.3G>C	p.Met1?	missense	1	Likely Pathogenic	0.000000
100.	c.2557G>A	p.G853S	missense	1	VUS	0.000008
101.	c.3763G>A	p.A1255T	missense	1	VUS favour pathogenic	0.000075
102.	c.3605G>A	p.C1202Y	missense	1	Likely Pathogenic	0.000000
103.	c.1960C>T	p.R654C	missense	1	VUS favour benign	0.000008
104.	c.566T>A	p.V189D	missense	1	VUS	0.000000
105.	c.3040delC	p.Leu1014TrpfsX6	frameshift	1	Pathogenic	0.000000
106.	c.2197C>T	p.R733C	missense	1	VUS	0.000085
107.	c.2436G>T	p.K812N	missense	1	VUS	0.000000
108.	c.2737+2T>A		essential splice site	1	Pathogenic	0.000000
109.	c.2953A>T	p.K985X	nonsense	1	Pathogenic	0.000000
110.	c.613C>T	p.Q205X	nonsense	1	Pathogenic	0.000000
111.	c.2308+1G>T		essential splice site	1	Pathogenic	0.000000
112.	c.3332_3335dupAGTG	p.W1112X	nonsense	1	Pathogenic	0.000000
113.	c.1168delC		frameshift	1	Pathogenic	0.000000
114.	c.1535T>A	p.L512Q	missense	1	VUS favour pathogenic	0.000000
115.	c.1624+2T>C		essential splice site	1	Pathogenic	0.000000
116.	c.3742G>A	p.G1248R	missense	1	VUS	0.000033
117.	c.103C>T	p.R35W	missense	1	VUS	0.000056
118.	c.1924C>T	p.Q642X	nonsense	1	Pathogenic	0.000000
119.	c.2654C>T	p.T885M	missense	1	VUS	0.000022
120.	c.932C>A	p.S311X	nonsense	1	Pathogenic	0.000000
121.	c.3373G>A	p.V1125M	missense	1	VUS favour pathogenic	0.000022
122.	c.1343T>C	p.F448S	missense	1	Likely Pathogenic	0.000000
123.	c.1586C>G	p.T529S	missense	1	VUS favour pathogenic	0.000000
124.	c.3548T>G	p.F1183C	missense	1	Likely Pathogenic	0.000000
125.	c.3791G>A	p.C1264Y	missense	1	VUS	0.000008
126.	c.966G>A	p.W322X	nonsense	1	Pathogenic	0.000000
127.	c.2737+1G>C		essential splice site	1	Pathogenic	0.000000
128.	c.3277G>T	p.G1093C	missense	1	VUS	0.000020
129.	c.2534_2538delGCGTC		frameshift	1	Pathogenic	0.000000
130.	c.223G>A	p.D75N	missense	1	VUS favour pathogenic	0.000091
131.	c.1678delG	p.Asp560ThrfsX19	frameshift	1	Pathogenic	0.000000
132.	c.2556_2557delinsTCT	p.Gly853fs	frameshift	1	Pathogenic	0.000000
133.	c.3181C>T	p.Q1061X	nonsense	1	Pathogenic	0.000016
134.	c.2517_2538del	p.Val840ThrfsX32	frameshift	1	Pathogenic	0.000000
135.	c.2149-1G>A		essential splice site	1	Pathogenic	0.000000
136.	c.821+1G>C		essential splice site	1	Pathogenic	0.000000
137.	c.2524_2525insT	p.Tyr842LeufsX42	frameshift	1	Pathogenic	0.000000
138.	c.333_334insT	p.E112X	nonsense	1	Pathogenic	0.000000
139.	c.2906-2A>G		essential splice site	1	Pathogenic	0.000000
140.	c.533delT	p.Val178GlyfsX7	frameshift	1	Pathogenic	0.000000
141.	c.1800delA		frameshift	1	Pathogenic	0.000000
142.	c.1273C>T	p.Q425X	nonsense	1	Pathogenic	0.000000
143.	c.1672G>A	p.A558T	missense	1	VUS	0.000008
144.	c.1456T>G	p.W486G	missense	1	Likely Pathogenic	0.000000
145.	c.2518G>A	p.V840M	missense	1	VUS	0.000016
146.	c.1090+1G>T		essential splice site	1	Pathogenic	0.000000
147.	c.3083C>G	p.T1028S	missense	1	VUS	0.000000
148.	c.1351+1G>A		essential splice site	1	Pathogenic	0.000000
149.	c.2528_2536delAGATGCGCG	p.Glu843_Arg845del	inframe	1	Pathogenic	0.000000
150.	c.3415G>A	p.V1139I	missense	1	VUS	0.000087
151.	c.2210C>T	p.T737M	missense	1	VUS	0.000050
152.	c.3476_3477delTT		frameshift	1	Pathogenic	0.000000
153.	c.3797G>A	p.C1266Y	missense	1	Likely Pathogenic	0.000000
154.	c.290C>T	p.A97V	missense	1	VUS favour pathogenic	0.000000
155.	c.373G>T	p.A125S	missense	1	VUS	0.000000
156.	c.2780_2781delCA		frameshift	1	Pathogenic	0.000000
157.	c.1188G>T	p.W396C	missense	1	VUS	0.000000
158.	c.1699_1700delGA	p.Glu567GlyfsX4	frameshift	1	Pathogenic	0.000000
159.	c.481C>A	p.P161T	missense	1	VUS favour pathogenic	0.000041
160.	c.436A>C	p.T146P	missense	1	VUS	0.000000
161.	c.506-1G>T		essential splice site	1	Pathogenic	0.000000
162.	c.1999_2000delinsG	p.Leu667AspfsX15	frameshift	1	Pathogenic	0.000000
163.	c.1021G>A	p.G341S	missense	1	VUS favour pathogenic	0.000025
164.	c.326C>T	p.A109V	missense	1	VUS	0.000000
165.	c.2040_2041insT	p.Val681CysfsX12	frameshift	1	Pathogenic	0.000000
166.	c.1000G>T	p.E334X	nonsense	1	Pathogenic	0.000000
167.	c.2723A>G	p.Y908C	missense	1	VUS	0.000062
168.	c.3580G>A	p.A1194T	missense	1	VUS	0.000008
169.	c.3335G>A	p.W1112X	nonsense	1	Pathogenic	0.000000
170.	c.2747G>A	p.W916X	nonsense	1	Pathogenic	0.000000
171.	c.2394_2395insT	p.Gly799TrpfsX34	frameshift	1	Pathogenic	0.000000
172.	c.931T>A	p.S311T	missense	1	VUS	0.000000
173.	c.3166_3167insG	p.Ala1056GlyfsX9	frameshift	1	Pathogenic	0.000000
174.	c.3476_3479dupTTAT	p.Pro1161TyrfsX9	frameshift	1	Pathogenic	0.000000
175.	c.2965G>T	p.E989X	nonsense	1	Pathogenic	0.000000
176.	c.821+2T>C		essential splice site	1	Pathogenic	0.000000
177.	c.2269G>A	p.V757M	missense	1	VUS	0.000066
178.	c.3811C>T	p.R1271X	nonsense	1	Pathogenic	0.000025
179.	c.932C>T	p.S311L	missense	1	VUS	0.000000
180.	c.1397T>A	p.M466K	missense	1	VUS	0.000008
181.	c.655-1G>A		essential splice site	1	Pathogenic	0.000000
182.	c.2993A>G	p.Q998R	missense	1	VUS favour pathogenic	0.000000
183.	c.2671C>T	p.R891W	missense	1	Likely Pathogenic	0.000031
184.	c.1841A>G	p.Y614C	missense	1	VUS favour pathogenic	0.000000
185.	c.3776delA		frameshift	1	Pathogenic	0.000000
186.	c.2828G>A	p.R943Q	missense	1	VUS	0.000025
187.	c.1213A>G	p.M405V	missense	1	Pathogenic	0.000000
188.	c.104G>A	p.R35Q	missense	1	VUS	0.000079
189.	c.3753T>G	p.Y1251X	nonsense	1	Pathogenic	0.000000
190.	c.2449C>T	p.R817W	missense	1	VUS	0.000000
191.	c.3825A>G	p.X1275TrpextX77	nonsense	1	Likely Pathogenic	0.000000
192.	c.451G>A	p.D151N	missense	1	VUS	0.000041
193.	c.2641G>A	p.V881I	missense	1	VUS	0.000018
194.	c.2939G>A	p.R980H	missense	1	VUS	0.000000
195.	c.1892delT		frameshift	1	Pathogenic	0.000000
196.	c.3815-1G>A		essential splice site	1	Pathogenic	0.000000
197.	c.2833_2834delCG		frameshift	1	Pathogenic	0.000000
198.	c.518C>A	p.T173N	missense	1	VUS	0.000000
199.	c.177_187del	p.Glu60AlafsX49	frameshift	1	Pathogenic	0.000000
200.	c.1950C>G	p.D650E	missense	1	VUS	0.000000
201.	c.1458-1G>A		essential splice site	1	Pathogenic	0.000000
202.	c.551_552insT	p.Lys185GlufsX56	frameshift	1	Pathogenic	0.000000
203.	c.2541C>A	p.Y847X	nonsense	1	Pathogenic	0.000000
204.	c.3331-1G>A		essential splice site	1	Pathogenic	0.000000
205.	c.3286G>T	p.E1096X	nonsense	1	Pathogenic	0.000000
206.	c.1505G>T	p.R502L	missense	1	VUS favour pathogenic	0.000000
207.	c.2048G>A	p.W683X	nonsense	1	Pathogenic	0.000000
208.	c.3288delG		frameshift	1	Pathogenic	0.000000
209.	c.2560A>G	p.M854V	missense	1	VUS	0.000000
210.	c.1156G>T	p.E386X	nonsense	1	Pathogenic	0.000000
211.	c.2459G>A	p.R820Q	missense	1	Likely Pathogenic	0.000016
212.	c.713G>A	p.R238H	missense	1	VUS	0.000074
213.	c.833delG	p.Gly278GlufsX22	frameshift	1	Pathogenic	0.000000
214.	c.2905+1G>C		essential splice site	1	Pathogenic	0.000000
215.	c.3098G>A	p.R1033Q	missense	1	VUS	0.000000
216.	c.1628delA		frameshift	1	Pathogenic	0.000000
217.	c.2610_2611insC	p.Ser871GlnfsX13	frameshift	1	Pathogenic	0.000000
218.	c.1090+1G>A		essential splice site	1	Pathogenic	0.000000
219.	c.3065G>A	p.R1022H	missense	1	VUS favour pathogenic	0.000000
220.	c.3746G>T	p.G1249V	missense	1	VUS	0.000000
221.	c.1418T>C	p.F473S	missense	1	VUS	0.000000
222.	c.3068_3069insA	p.Asn1023LysfsX28	frameshift	1	Pathogenic	0.000000
223.	c.853G>A	p.D285N	missense	1	VUS	0.000000
224.	c.3694A>T	p.K1232X	nonsense	1	Pathogenic	0.000000
225.	c.2113_2114insA	p.Thr705AsnfsX3	frameshift	1	Pathogenic	0.000000
226.	c.1778C>T	p.S593F	missense	1	VUS favour pathogenic	0.000034
227.	c.3281A>T	p.N1094I	missense	1	VUS	0.000000
228.	c.1351+2T>C		essential splice site	1	Pathogenic	0.000000
229.	c.3413G>C	p.R1138P	missense	1	VUS	0.000000
230.	c.3253G>T	p.E1085X	nonsense	1	Pathogenic	0.000000
231.	c.2312T>C	p.V771A	missense	1	VUS	0.000000
232.	c.2875_2876delAC	p.Thr959GlyfsX91	frameshift	1	Pathogenic	0.000000
233.	c.3690_3691delCA	p.Phe1230LeufsX11	frameshift	1	Pathogenic	0.000000
234.	c.2437A>T	p.K813X	nonsense	1	Pathogenic	0.000000
235.	c.993_994insT	p.E332X	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.