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.3226_3227insT		frameshift	6	Pathogenic	0.000000
16.	c.1505G>A	p.R502Q	missense	6	Pathogenic	0.000000
17.	c.2864_2865delCT		frameshift	6	Pathogenic	0.000000
18.	c.2308G>A	p.D770N	missense	6	Likely Pathogenic	0.000008
19.	c.2374T>C	p.W792R	missense	5	Likely Pathogenic	0.000000
20.	c.913_914delTT		frameshift	5	Pathogenic	0.000000
21.	c.2454G>A	p.W818X	nonsense	4	Pathogenic	0.000000
22.	c.3064C>T	p.R1022C	missense	4	VUS favour pathogenic	0.000008
23.	c.2182G>T	p.E728X	nonsense	4	Pathogenic	0.000000
24.	c.3742_3759dup	p.Gly1248_Cys1253dup	inframe	4	Likely Pathogenic	0.000000
25.	c.2573G>A	p.S858N	missense	4	VUS favour pathogenic	0.000000
26.	c.2096delC		frameshift	4	Pathogenic	0.000000
27.	c.26-2A>G		essential splice site	4	Pathogenic	0.000051
28.	c.1483C>G	p.R495G	missense	4	Likely Pathogenic	0.000000
29.	c.821+1G>A		essential splice site	4	Pathogenic	0.000043
30.	c.2905+1G>A		essential splice site	4	Pathogenic	0.000000
31.	c.1591G>A	p.G531R	missense	3	VUS favour pathogenic	0.000017
32.	c.3767_3769delCCA	p.Thr1256del	inframe	3	Likely Pathogenic	0.000000
33.	c.2920C>T	p.Q974X	nonsense	3	Pathogenic	0.000000
34.	c.2905C>T	p.Q969X	nonsense	3	Pathogenic	0.000000
35.	c.710A>C	p.Y237S	missense	3	Likely Pathogenic	0.000000
36.	c.2450G>A	p.R817Q	missense	3	VUS favour pathogenic	0.000016
37.	c.3491-2A>T		essential splice site	3	Pathogenic	0.000000
38.	c.3233G>A	p.W1078X	nonsense	3	Pathogenic	0.000022
39.	c.2311_2312insG	p.Val771GlyfsX62	frameshift	3	Pathogenic	0.000000
40.	c.1828G>A	p.D610N	missense	3	VUS	0.000000
41.	c.355G>A	p.E119K	missense	3	VUS	0.000000
42.	c.3190+1G>A		essential splice site	3	Pathogenic	0.000000
43.	c.2873C>T	p.T958I	missense	3	VUS favour benign	0.000065
44.	c.772+1G>A		essential splice site	2	Pathogenic	0.000000
45.	c.2604_2605delinsA	p.S871fs	frameshift	2	Pathogenic	0.000000
46.	c.814C>T	p.R272C	missense	2	VUS	0.000083
47.	c.1790G>A	p.R597Q	missense	2	VUS favour pathogenic	0.000000
48.	c.1483C>T	p.R495W	missense	2	VUS favour pathogenic	0.000000
49.	c.2320G>A	p.A774T	missense	2	VUS	0.000000
50.	c.2943_2947delGACCA		frameshift	2	Pathogenic	0.000000
51.	c.1897+1G>A		essential splice site	2	Pathogenic	0.000000
52.	c.927-2A>G		essential splice site	2	Pathogenic	0.000000
53.	c.2558delG		frameshift	2	Pathogenic	0.000000
54.	c.1828G>C	p.D610H	missense	2	VUS favour benign	0.000058
55.	c.2882C>T	p.P961L	missense	2	VUS	0.000048
56.	c.1037G>A	p.R346H	missense	2	VUS	0.000000
57.	c.1863delC	p.Phe621LeufsX42	frameshift	2	Pathogenic	0.000000
58.	c.532G>A	p.V178M	missense	2	VUS favour pathogenic	0.000020
59.	c.1210C>T	p.Q404X	nonsense	2	Pathogenic	0.000000
60.	c.1869C>A	p.C623X	nonsense	2	Pathogenic	0.000000
61.	c.436_437insA	p.Thr146AsnfsX7	frameshift	2	Pathogenic	0.000000
62.	c.3624delC		frameshift	2	Pathogenic	0.000000
63.	c.3190+2T>G		essential splice site	2	Pathogenic	0.000016
64.	c.3192_3193insC	p.Lys1065GlnfsX12	frameshift	2	Pathogenic	0.000000
65.	c.1934C>T	p.P645L	missense	2	VUS	0.000000
66.	c.999C>G	p.Y333X	nonsense	2	Pathogenic	0.000000
67.	c.3624_3625insC	p.Lys1209GlnfsX33	frameshift	2	Pathogenic	0.000000
68.	c.1766G>A	p.R589H	missense	2	VUS	0.000000
69.	c.1513_1515delAAG		inframe	2	VUS favour pathogenic	0.000000
70.	c.636C>G	p.S212R	missense	2	VUS favour pathogenic	0.000000
71.	c.1895delT	p.Met632ArgfsX31	frameshift	2	Pathogenic	0.000000
72.	c.3627+1G>A		essential splice site	2	Pathogenic	0.000000
73.	c.1357_1358delCC		frameshift	2	Pathogenic	0.000000
74.	c.1397T>A	p.M466K	missense	1	VUS	0.000008
75.	c.655-1G>A		essential splice site	1	Pathogenic	0.000000
76.	c.2993A>G	p.Q998R	missense	1	VUS favour pathogenic	0.000000
77.	c.2269G>A	p.V757M	missense	1	VUS	0.000066
78.	c.3811C>T	p.R1271X	nonsense	1	Pathogenic	0.000025
79.	c.932C>T	p.S311L	missense	1	VUS	0.000000
80.	c.2828G>A	p.R943Q	missense	1	VUS	0.000025
81.	c.1213A>G	p.M405V	missense	1	Pathogenic	0.000000
82.	c.2671C>T	p.R891W	missense	1	Likely Pathogenic	0.000031
83.	c.1841A>G	p.Y614C	missense	1	VUS favour pathogenic	0.000000
84.	c.3776delA		frameshift	1	Pathogenic	0.000000
85.	c.2939G>A	p.R980H	missense	1	VUS	0.000000
86.	c.1892delT		frameshift	1	Pathogenic	0.000000
87.	c.3815-1G>A		essential splice site	1	Pathogenic	0.000000
88.	c.2833_2834delCG		frameshift	1	Pathogenic	0.000000
89.	c.104G>A	p.R35Q	missense	1	VUS	0.000079
90.	c.3753T>G	p.Y1251X	nonsense	1	Pathogenic	0.000000
91.	c.2449C>T	p.R817W	missense	1	VUS	0.000000
92.	c.3825A>G	p.X1275TrpextX77	nonsense	1	Likely Pathogenic	0.000000
93.	c.451G>A	p.D151N	missense	1	VUS	0.000041
94.	c.2641G>A	p.V881I	missense	1	VUS	0.000018
95.	c.1950C>G	p.D650E	missense	1	VUS	0.000000
96.	c.1458-1G>A		essential splice site	1	Pathogenic	0.000000
97.	c.518C>A	p.T173N	missense	1	VUS	0.000000
98.	c.177_187del	p.Glu60AlafsX49	frameshift	1	Pathogenic	0.000000
99.	c.3331-1G>A		essential splice site	1	Pathogenic	0.000000
100.	c.551_552insT	p.Lys185GlufsX56	frameshift	1	Pathogenic	0.000000
101.	c.2541C>A	p.Y847X	nonsense	1	Pathogenic	0.000000
102.	c.2048G>A	p.W683X	nonsense	1	Pathogenic	0.000000
103.	c.3286G>T	p.E1096X	nonsense	1	Pathogenic	0.000000
104.	c.1505G>T	p.R502L	missense	1	VUS favour pathogenic	0.000000
105.	c.3288delG		frameshift	1	Pathogenic	0.000000
106.	c.713G>A	p.R238H	missense	1	VUS	0.000074
107.	c.2560A>G	p.M854V	missense	1	VUS	0.000000
108.	c.1156G>T	p.E386X	nonsense	1	Pathogenic	0.000000
109.	c.2459G>A	p.R820Q	missense	1	Likely Pathogenic	0.000016
110.	c.1090+1G>A		essential splice site	1	Pathogenic	0.000000
111.	c.3065G>A	p.R1022H	missense	1	VUS favour pathogenic	0.000000
112.	c.3746G>T	p.G1249V	missense	1	VUS	0.000000
113.	c.833delG	p.Gly278GlufsX22	frameshift	1	Pathogenic	0.000000
114.	c.2905+1G>C		essential splice site	1	Pathogenic	0.000000
115.	c.3098G>A	p.R1033Q	missense	1	VUS	0.000000
116.	c.1628delA		frameshift	1	Pathogenic	0.000000
117.	c.2610_2611insC	p.Ser871GlnfsX13	frameshift	1	Pathogenic	0.000000
118.	c.853G>A	p.D285N	missense	1	VUS	0.000000
119.	c.3694A>T	p.K1232X	nonsense	1	Pathogenic	0.000000
120.	c.2113_2114insA	p.Thr705AsnfsX3	frameshift	1	Pathogenic	0.000000
121.	c.1778C>T	p.S593F	missense	1	VUS favour pathogenic	0.000034
122.	c.3281A>T	p.N1094I	missense	1	VUS	0.000000
123.	c.1351+2T>C		essential splice site	1	Pathogenic	0.000000
124.	c.1418T>C	p.F473S	missense	1	VUS	0.000000
125.	c.3068_3069insA	p.Asn1023LysfsX28	frameshift	1	Pathogenic	0.000000
126.	c.3690_3691delCA	p.Phe1230LeufsX11	frameshift	1	Pathogenic	0.000000
127.	c.2437A>T	p.K813X	nonsense	1	Pathogenic	0.000000
128.	c.3413G>C	p.R1138P	missense	1	VUS	0.000000
129.	c.3253G>T	p.E1085X	nonsense	1	Pathogenic	0.000000
130.	c.2312T>C	p.V771A	missense	1	VUS	0.000000
131.	c.2875_2876delAC	p.Thr959GlyfsX91	frameshift	1	Pathogenic	0.000000
132.	c.993_994insT	p.E332X	nonsense	1	Pathogenic	0.000000
133.	c.2234A>G	p.D745G	missense	1	VUS	0.000000
134.	c.3065G>C	p.R1022P	missense	1	VUS favour pathogenic	0.000025
135.	c.844C>T	p.R282W	missense	1	VUS favour pathogenic	0.000000
136.	c.1693A>T	p.K565X	nonsense	1	Pathogenic	0.000000
137.	c.1591G>C	p.G531R	missense	1	VUS favour pathogenic	0.000017
138.	c.1540A>G	p.I514V	missense	1	VUS	0.000008
139.	c.1575T>G	p.Y525X	nonsense	1	Pathogenic	0.000000
140.	c.1038_1042dupCGGCA		frameshift	1	Pathogenic	0.000008
141.	c.1358C>T	p.P453L	missense	1	VUS	0.000008
142.	c.2490_2491insT	p.His831SerfsTer2	frameshift	1	Pathogenic	0.000024
143.	c.3049G>A	p.E1017K	missense	1	VUS favour benign	0.000085
144.	c.1224-2A>G		essential splice site	1	Pathogenic	0.000000
145.	c.2163delC	p.Glu722ArgfsX32	frameshift	1	Pathogenic	0.000000
146.	c.2308+1G>A		essential splice site	1	Pathogenic	0.000000
147.	c.2938C>T	p.R980C	missense	1	VUS	0.000062
148.	c.2170C>T	p.R724W	missense	1	VUS	0.000019
149.	c.3408C>A	p.Y1136X	nonsense	1	Pathogenic	0.000000
150.	c.3735delC		frameshift	1	Likely Pathogenic	0.000000
151.	c.2533C>T	p.R845C	missense	1	VUS favour pathogenic	0.000000
152.	c.3676C>T	p.R1226C	missense	1	VUS	0.000058
153.	c.2013_2016delinsGG	p.Pro672AspfsX20	frameshift	1	Pathogenic	0.000000
154.	c.3G>C	p.Met1?	missense	1	Likely Pathogenic	0.000000
155.	c.2557G>A	p.G853S	missense	1	VUS	0.000008
156.	c.3763G>A	p.A1255T	missense	1	VUS favour pathogenic	0.000075
157.	c.431_432delGT	p.Gly144AlafsX8	frameshift	1	Pathogenic	0.000000
158.	c.1294G>A	p.A432T	missense	1	VUS	0.000037
159.	c.459delC		frameshift	1	Pathogenic	0.000000
160.	c.2525A>G	p.Y842C	missense	1	VUS	0.000000
161.	c.566T>A	p.V189D	missense	1	VUS	0.000000
162.	c.3040delC	p.Leu1014TrpfsX6	frameshift	1	Pathogenic	0.000000
163.	c.2197C>T	p.R733C	missense	1	VUS	0.000085
164.	c.2436G>T	p.K812N	missense	1	VUS	0.000000
165.	c.2737+2T>A		essential splice site	1	Pathogenic	0.000000
166.	c.3605G>A	p.C1202Y	missense	1	Likely Pathogenic	0.000000
167.	c.1960C>T	p.R654C	missense	1	VUS favour benign	0.000008
168.	c.2308+1G>T		essential splice site	1	Pathogenic	0.000000
169.	c.3332_3335dupAGTG	p.W1112X	nonsense	1	Pathogenic	0.000000
170.	c.2953A>T	p.K985X	nonsense	1	Pathogenic	0.000000
171.	c.613C>T	p.Q205X	nonsense	1	Pathogenic	0.000000
172.	c.1535T>A	p.L512Q	missense	1	VUS favour pathogenic	0.000000
173.	c.1624+2T>C		essential splice site	1	Pathogenic	0.000000
174.	c.1168delC		frameshift	1	Pathogenic	0.000000
175.	c.3742G>A	p.G1248R	missense	1	VUS	0.000033
176.	c.932C>A	p.S311X	nonsense	1	Pathogenic	0.000000
177.	c.3373G>A	p.V1125M	missense	1	VUS favour pathogenic	0.000022
178.	c.1343T>C	p.F448S	missense	1	Likely Pathogenic	0.000000
179.	c.1586C>G	p.T529S	missense	1	VUS favour pathogenic	0.000000
180.	c.103C>T	p.R35W	missense	1	VUS	0.000056
181.	c.1924C>T	p.Q642X	nonsense	1	Pathogenic	0.000000
182.	c.2654C>T	p.T885M	missense	1	VUS	0.000022
183.	c.3277G>T	p.G1093C	missense	1	VUS	0.000020
184.	c.2534_2538delGCGTC		frameshift	1	Pathogenic	0.000000
185.	c.3548T>G	p.F1183C	missense	1	Likely Pathogenic	0.000000
186.	c.3791G>A	p.C1264Y	missense	1	VUS	0.000008
187.	c.966G>A	p.W322X	nonsense	1	Pathogenic	0.000000
188.	c.2737+1G>C		essential splice site	1	Pathogenic	0.000000
189.	c.2556_2557delinsTCT	p.Gly853fs	frameshift	1	Pathogenic	0.000000
190.	c.3181C>T	p.Q1061X	nonsense	1	Pathogenic	0.000016
191.	c.2517_2538del	p.Val840ThrfsX32	frameshift	1	Pathogenic	0.000000
192.	c.2149-1G>A		essential splice site	1	Pathogenic	0.000000
193.	c.821+1G>C		essential splice site	1	Pathogenic	0.000000
194.	c.223G>A	p.D75N	missense	1	VUS favour pathogenic	0.000091
195.	c.1678delG	p.Asp560ThrfsX19	frameshift	1	Pathogenic	0.000000
196.	c.2906-2A>G		essential splice site	1	Pathogenic	0.000000
197.	c.533delT	p.Val178GlyfsX7	frameshift	1	Pathogenic	0.000000
198.	c.2524_2525insT	p.Tyr842LeufsX42	frameshift	1	Pathogenic	0.000000
199.	c.333_334insT	p.E112X	nonsense	1	Pathogenic	0.000000
200.	c.1800delA		frameshift	1	Pathogenic	0.000000
201.	c.1273C>T	p.Q425X	nonsense	1	Pathogenic	0.000000
202.	c.2518G>A	p.V840M	missense	1	VUS	0.000016
203.	c.1090+1G>T		essential splice site	1	Pathogenic	0.000000
204.	c.1672G>A	p.A558T	missense	1	VUS	0.000008
205.	c.1456T>G	p.W486G	missense	1	Likely Pathogenic	0.000000
206.	c.3797G>A	p.C1266Y	missense	1	Likely Pathogenic	0.000000
207.	c.290C>T	p.A97V	missense	1	VUS favour pathogenic	0.000000
208.	c.373G>T	p.A125S	missense	1	VUS	0.000000
209.	c.2780_2781delCA		frameshift	1	Pathogenic	0.000000
210.	c.3083C>G	p.T1028S	missense	1	VUS	0.000000
211.	c.1351+1G>A		essential splice site	1	Pathogenic	0.000000
212.	c.2528_2536delAGATGCGCG	p.Glu843_Arg845del	inframe	1	Pathogenic	0.000000
213.	c.3415G>A	p.V1139I	missense	1	VUS	0.000087
214.	c.2210C>T	p.T737M	missense	1	VUS	0.000050
215.	c.3476_3477delTT		frameshift	1	Pathogenic	0.000000
216.	c.1021G>A	p.G341S	missense	1	VUS favour pathogenic	0.000025
217.	c.326C>T	p.A109V	missense	1	VUS	0.000000
218.	c.2040_2041insT	p.Val681CysfsX12	frameshift	1	Pathogenic	0.000000
219.	c.1000G>T	p.E334X	nonsense	1	Pathogenic	0.000000
220.	c.2723A>G	p.Y908C	missense	1	VUS	0.000062
221.	c.3580G>A	p.A1194T	missense	1	VUS	0.000008
222.	c.3335G>A	p.W1112X	nonsense	1	Pathogenic	0.000000
223.	c.1188G>T	p.W396C	missense	1	VUS	0.000000
224.	c.1699_1700delGA	p.Glu567GlyfsX4	frameshift	1	Pathogenic	0.000000
225.	c.481C>A	p.P161T	missense	1	VUS favour pathogenic	0.000041
226.	c.436A>C	p.T146P	missense	1	VUS	0.000000
227.	c.506-1G>T		essential splice site	1	Pathogenic	0.000000
228.	c.1999_2000delinsG	p.Leu667AspfsX15	frameshift	1	Pathogenic	0.000000
229.	c.2394_2395insT	p.Gly799TrpfsX34	frameshift	1	Pathogenic	0.000000
230.	c.931T>A	p.S311T	missense	1	VUS	0.000000
231.	c.3166_3167insG	p.Ala1056GlyfsX9	frameshift	1	Pathogenic	0.000000
232.	c.2747G>A	p.W916X	nonsense	1	Pathogenic	0.000000
233.	c.821+2T>C		essential splice site	1	Pathogenic	0.000000
234.	c.3476_3479dupTTAT	p.Pro1161TyrfsX9	frameshift	1	Pathogenic	0.000000
235.	c.2965G>T	p.E989X	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.