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