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