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