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