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.2670G>A	p.W890X	nonsense	7	Pathogenic	0.000000
13.	c.2827C>T	p.R943X	nonsense	7	Pathogenic	0.000017
14.	c.442G>A	p.G148R	missense	7	VUS favour pathogenic	0.000042
15.	c.2864_2865delCT		frameshift	6	Pathogenic	0.000000
16.	c.3226_3227insT		frameshift	6	Pathogenic	0.000000
17.	c.2308G>A	p.D770N	missense	6	Likely Pathogenic	0.000008
18.	c.1505G>A	p.R502Q	missense	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.821+1G>A		essential splice site	4	Pathogenic	0.000043
22.	c.2454G>A	p.W818X	nonsense	4	Pathogenic	0.000000
23.	c.2905+1G>A		essential splice site	4	Pathogenic	0.000000
24.	c.2573G>A	p.S858N	missense	4	VUS favour pathogenic	0.000000
25.	c.2096delC		frameshift	4	Pathogenic	0.000000
26.	c.3064C>T	p.R1022C	missense	4	VUS favour pathogenic	0.000008
27.	c.2182G>T	p.E728X	nonsense	4	Pathogenic	0.000000
28.	c.1483C>G	p.R495G	missense	4	Likely Pathogenic	0.000000
29.	c.26-2A>G		essential splice site	4	Pathogenic	0.000051
30.	c.3742_3759dup	p.Gly1248_Cys1253dup	inframe	4	Likely Pathogenic	0.000000
31.	c.355G>A	p.E119K	missense	3	VUS	0.000000
32.	c.3190+1G>A		essential splice site	3	Pathogenic	0.000000
33.	c.2873C>T	p.T958I	missense	3	VUS favour benign	0.000065
34.	c.2920C>T	p.Q974X	nonsense	3	Pathogenic	0.000000
35.	c.1828G>A	p.D610N	missense	3	VUS	0.000000
36.	c.3233G>A	p.W1078X	nonsense	3	Pathogenic	0.000022
37.	c.2450G>A	p.R817Q	missense	3	VUS favour pathogenic	0.000016
38.	c.1591G>A	p.G531R	missense	3	VUS favour pathogenic	0.000017
39.	c.710A>C	p.Y237S	missense	3	Likely Pathogenic	0.000000
40.	c.2905C>T	p.Q969X	nonsense	3	Pathogenic	0.000000
41.	c.3491-2A>T		essential splice site	3	Pathogenic	0.000000
42.	c.2311_2312insG	p.Val771GlyfsX62	frameshift	3	Pathogenic	0.000000
43.	c.3767_3769delCCA	p.Thr1256del	inframe	3	Likely Pathogenic	0.000000
44.	c.3192_3193insC	p.Lys1065GlnfsX12	frameshift	2	Pathogenic	0.000000
45.	c.3624_3625insC	p.Lys1209GlnfsX33	frameshift	2	Pathogenic	0.000000
46.	c.999C>G	p.Y333X	nonsense	2	Pathogenic	0.000000
47.	c.2320G>A	p.A774T	missense	2	VUS	0.000000
48.	c.532G>A	p.V178M	missense	2	VUS favour pathogenic	0.000020
49.	c.814C>T	p.R272C	missense	2	VUS	0.000083
50.	c.1895delT	p.Met632ArgfsX31	frameshift	2	Pathogenic	0.000000
51.	c.636C>G	p.S212R	missense	2	VUS favour pathogenic	0.000000
52.	c.2943_2947delGACCA		frameshift	2	Pathogenic	0.000000
53.	c.2558delG		frameshift	2	Pathogenic	0.000000
54.	c.1513_1515delAAG		inframe	2	VUS favour pathogenic	0.000000
55.	c.1037G>A	p.R346H	missense	2	VUS	0.000000
56.	c.1828G>C	p.D610H	missense	2	VUS favour benign	0.000058
57.	c.772+1G>A		essential splice site	2	Pathogenic	0.000000
58.	c.927-2A>G		essential splice site	2	Pathogenic	0.000000
59.	c.2604_2605delinsA	p.S871fs	frameshift	2	Pathogenic	0.000000
60.	c.436_437insA	p.Thr146AsnfsX7	frameshift	2	Pathogenic	0.000000
61.	c.3627+1G>A		essential splice site	2	Pathogenic	0.000000
62.	c.1934C>T	p.P645L	missense	2	VUS	0.000000
63.	c.1357_1358delCC		frameshift	2	Pathogenic	0.000000
64.	c.1210C>T	p.Q404X	nonsense	2	Pathogenic	0.000000
65.	c.1897+1G>A		essential splice site	2	Pathogenic	0.000000
66.	c.3190+2T>G		essential splice site	2	Pathogenic	0.000016
67.	c.1790G>A	p.R597Q	missense	2	VUS favour pathogenic	0.000000
68.	c.1869C>A	p.C623X	nonsense	2	Pathogenic	0.000000
69.	c.1483C>T	p.R495W	missense	2	VUS favour pathogenic	0.000000
70.	c.1766G>A	p.R589H	missense	2	VUS	0.000000
71.	c.1863delC	p.Phe621LeufsX42	frameshift	2	Pathogenic	0.000000
72.	c.2882C>T	p.P961L	missense	2	VUS	0.000048
73.	c.3624delC		frameshift	2	Pathogenic	0.000000
74.	c.2556_2557delinsTCT	p.Gly853fs	frameshift	1	Pathogenic	0.000000
75.	c.2149-1G>A		essential splice site	1	Pathogenic	0.000000
76.	c.1678delG	p.Asp560ThrfsX19	frameshift	1	Pathogenic	0.000000
77.	c.2308+1G>T		essential splice site	1	Pathogenic	0.000000
78.	c.2906-2A>G		essential splice site	1	Pathogenic	0.000000
79.	c.2560A>G	p.M854V	missense	1	VUS	0.000000
80.	c.533delT	p.Val178GlyfsX7	frameshift	1	Pathogenic	0.000000
81.	c.1213A>G	p.M405V	missense	1	Pathogenic	0.000000
82.	c.2524_2525insT	p.Tyr842LeufsX42	frameshift	1	Pathogenic	0.000000
83.	c.333_334insT	p.E112X	nonsense	1	Pathogenic	0.000000
84.	c.713G>A	p.R238H	missense	1	VUS	0.000074
85.	c.3746G>T	p.G1249V	missense	1	VUS	0.000000
86.	c.3065G>A	p.R1022H	missense	1	VUS favour pathogenic	0.000000
87.	c.3098G>A	p.R1033Q	missense	1	VUS	0.000000
88.	c.1343T>C	p.F448S	missense	1	Likely Pathogenic	0.000000
89.	c.833delG	p.Gly278GlufsX22	frameshift	1	Pathogenic	0.000000
90.	c.3373G>A	p.V1125M	missense	1	VUS favour pathogenic	0.000022
91.	c.1892delT		frameshift	1	Pathogenic	0.000000
92.	c.2610_2611insC	p.Ser871GlnfsX13	frameshift	1	Pathogenic	0.000000
93.	c.3694A>T	p.K1232X	nonsense	1	Pathogenic	0.000000
94.	c.3476_3477delTT		frameshift	1	Pathogenic	0.000000
95.	c.1418T>C	p.F473S	missense	1	VUS	0.000000
96.	c.2534_2538delGCGTC		frameshift	1	Pathogenic	0.000000
97.	c.481C>A	p.P161T	missense	1	VUS favour pathogenic	0.000041
98.	c.1021G>A	p.G341S	missense	1	VUS favour pathogenic	0.000025
99.	c.1624+2T>C		essential splice site	1	Pathogenic	0.000000
100.	c.932C>A	p.S311X	nonsense	1	Pathogenic	0.000000
101.	c.1999_2000delinsG	p.Leu667AspfsX15	frameshift	1	Pathogenic	0.000000
102.	c.1000G>T	p.E334X	nonsense	1	Pathogenic	0.000000
103.	c.1699_1700delGA	p.Glu567GlyfsX4	frameshift	1	Pathogenic	0.000000
104.	c.1156G>T	p.E386X	nonsense	1	Pathogenic	0.000000
105.	c.2394_2395insT	p.Gly799TrpfsX34	frameshift	1	Pathogenic	0.000000
106.	c.1540A>G	p.I514V	missense	1	VUS	0.000008
107.	c.3166_3167insG	p.Ala1056GlyfsX9	frameshift	1	Pathogenic	0.000000
108.	c.3286G>T	p.E1096X	nonsense	1	Pathogenic	0.000000
109.	c.2747G>A	p.W916X	nonsense	1	Pathogenic	0.000000
110.	c.1456T>G	p.W486G	missense	1	Likely Pathogenic	0.000000
111.	c.821+2T>C		essential splice site	1	Pathogenic	0.000000
112.	c.1628delA		frameshift	1	Pathogenic	0.000000
113.	c.2938C>T	p.R980C	missense	1	VUS	0.000062
114.	c.2170C>T	p.R724W	missense	1	VUS	0.000019
115.	c.2163delC	p.Glu722ArgfsX32	frameshift	1	Pathogenic	0.000000
116.	c.3476_3479dupTTAT	p.Pro1161TyrfsX9	frameshift	1	Pathogenic	0.000000
117.	c.3676C>T	p.R1226C	missense	1	VUS	0.000058
118.	c.1358C>T	p.P453L	missense	1	VUS	0.000008
119.	c.2533C>T	p.R845C	missense	1	VUS favour pathogenic	0.000000
120.	c.2965G>T	p.E989X	nonsense	1	Pathogenic	0.000000
121.	c.3049G>A	p.E1017K	missense	1	VUS favour benign	0.000085
122.	c.2013_2016delinsGG	p.Pro672AspfsX20	frameshift	1	Pathogenic	0.000000
123.	c.1038_1042dupCGGCA		frameshift	1	Pathogenic	0.000008
124.	c.3797G>A	p.C1266Y	missense	1	Likely Pathogenic	0.000000
125.	c.1294G>A	p.A432T	missense	1	VUS	0.000037
126.	c.431_432delGT	p.Gly144AlafsX8	frameshift	1	Pathogenic	0.000000
127.	c.2557G>A	p.G853S	missense	1	VUS	0.000008
128.	c.3753T>G	p.Y1251X	nonsense	1	Pathogenic	0.000000
129.	c.326C>T	p.A109V	missense	1	VUS	0.000000
130.	c.2234A>G	p.D745G	missense	1	VUS	0.000000
131.	c.1800delA		frameshift	1	Pathogenic	0.000000
132.	c.2436G>T	p.K812N	missense	1	VUS	0.000000
133.	c.3580G>A	p.A1194T	missense	1	VUS	0.000008
134.	c.436A>C	p.T146P	missense	1	VUS	0.000000
135.	c.931T>A	p.S311T	missense	1	VUS	0.000000
136.	c.3825A>G	p.X1275TrpextX77	nonsense	1	Likely Pathogenic	0.000000
137.	c.177_187del	p.Glu60AlafsX49	frameshift	1	Pathogenic	0.000000
138.	c.1458-1G>A		essential splice site	1	Pathogenic	0.000000
139.	c.3331-1G>A		essential splice site	1	Pathogenic	0.000000
140.	c.103C>T	p.R35W	missense	1	VUS	0.000056
141.	c.1586C>G	p.T529S	missense	1	VUS favour pathogenic	0.000000
142.	c.2490_2491insT	p.His831SerfsTer2	frameshift	1	Pathogenic	0.000024
143.	c.844C>T	p.R282W	missense	1	VUS favour pathogenic	0.000000
144.	c.2654C>T	p.T885M	missense	1	VUS	0.000022
145.	c.655-1G>A		essential splice site	1	Pathogenic	0.000000
146.	c.551_552insT	p.Lys185GlufsX56	frameshift	1	Pathogenic	0.000000
147.	c.1224-2A>G		essential splice site	1	Pathogenic	0.000000
148.	c.2541C>A	p.Y847X	nonsense	1	Pathogenic	0.000000
149.	c.3811C>T	p.R1271X	nonsense	1	Pathogenic	0.000025
150.	c.3776delA		frameshift	1	Pathogenic	0.000000
151.	c.3791G>A	p.C1264Y	missense	1	VUS	0.000008
152.	c.3548T>G	p.F1183C	missense	1	Likely Pathogenic	0.000000
153.	c.3277G>T	p.G1093C	missense	1	VUS	0.000020
154.	c.2671C>T	p.R891W	missense	1	Likely Pathogenic	0.000031
155.	c.966G>A	p.W322X	nonsense	1	Pathogenic	0.000000
156.	c.1505G>T	p.R502L	missense	1	VUS favour pathogenic	0.000000
157.	c.2833_2834delCG		frameshift	1	Pathogenic	0.000000
158.	c.821+1G>C		essential splice site	1	Pathogenic	0.000000
159.	c.2641G>A	p.V881I	missense	1	VUS	0.000018
160.	c.2517_2538del	p.Val840ThrfsX32	frameshift	1	Pathogenic	0.000000
161.	c.2449C>T	p.R817W	missense	1	VUS	0.000000
162.	c.3742G>A	p.G1248R	missense	1	VUS	0.000033
163.	c.1778C>T	p.S593F	missense	1	VUS favour pathogenic	0.000034
164.	c.518C>A	p.T173N	missense	1	VUS	0.000000
165.	c.2905+1G>C		essential splice site	1	Pathogenic	0.000000
166.	c.2113_2114insA	p.Thr705AsnfsX3	frameshift	1	Pathogenic	0.000000
167.	c.1351+2T>C		essential splice site	1	Pathogenic	0.000000
168.	c.3068_3069insA	p.Asn1023LysfsX28	frameshift	1	Pathogenic	0.000000
169.	c.1168delC		frameshift	1	Pathogenic	0.000000
170.	c.2875_2876delAC	p.Thr959GlyfsX91	frameshift	1	Pathogenic	0.000000
171.	c.2518G>A	p.V840M	missense	1	VUS	0.000016
172.	c.3690_3691delCA	p.Phe1230LeufsX11	frameshift	1	Pathogenic	0.000000
173.	c.2437A>T	p.K813X	nonsense	1	Pathogenic	0.000000
174.	c.1672G>A	p.A558T	missense	1	VUS	0.000008
175.	c.3253G>T	p.E1085X	nonsense	1	Pathogenic	0.000000
176.	c.1924C>T	p.Q642X	nonsense	1	Pathogenic	0.000000
177.	c.290C>T	p.A97V	missense	1	VUS favour pathogenic	0.000000
178.	c.3083C>G	p.T1028S	missense	1	VUS	0.000000
179.	c.2459G>A	p.R820Q	missense	1	Likely Pathogenic	0.000016
180.	c.993_994insT	p.E332X	nonsense	1	Pathogenic	0.000000
181.	c.3415G>A	p.V1139I	missense	1	VUS	0.000087
182.	c.2210C>T	p.T737M	missense	1	VUS	0.000050
183.	c.2528_2536delAGATGCGCG	p.Glu843_Arg845del	inframe	1	Pathogenic	0.000000
184.	c.373G>T	p.A125S	missense	1	VUS	0.000000
185.	c.2723A>G	p.Y908C	missense	1	VUS	0.000062
186.	c.3408C>A	p.Y1136X	nonsense	1	Pathogenic	0.000000
187.	c.2040_2041insT	p.Val681CysfsX12	frameshift	1	Pathogenic	0.000000
188.	c.1090+1G>A		essential splice site	1	Pathogenic	0.000000
189.	c.3288delG		frameshift	1	Pathogenic	0.000000
190.	c.1188G>T	p.W396C	missense	1	VUS	0.000000
191.	c.506-1G>T		essential splice site	1	Pathogenic	0.000000
192.	c.853G>A	p.D285N	missense	1	VUS	0.000000
193.	c.459delC		frameshift	1	Pathogenic	0.000000
194.	c.3281A>T	p.N1094I	missense	1	VUS	0.000000
195.	c.2048G>A	p.W683X	nonsense	1	Pathogenic	0.000000
196.	c.3763G>A	p.A1255T	missense	1	VUS favour pathogenic	0.000075
197.	c.1960C>T	p.R654C	missense	1	VUS favour benign	0.000008
198.	c.2312T>C	p.V771A	missense	1	VUS	0.000000
199.	c.3413G>C	p.R1138P	missense	1	VUS	0.000000
200.	c.3G>C	p.Met1?	missense	1	Likely Pathogenic	0.000000
201.	c.3040delC	p.Leu1014TrpfsX6	frameshift	1	Pathogenic	0.000000
202.	c.2269G>A	p.V757M	missense	1	VUS	0.000066
203.	c.2737+2T>A		essential splice site	1	Pathogenic	0.000000
204.	c.3605G>A	p.C1202Y	missense	1	Likely Pathogenic	0.000000
205.	c.1090+1G>T		essential splice site	1	Pathogenic	0.000000
206.	c.1397T>A	p.M466K	missense	1	VUS	0.000008
207.	c.613C>T	p.Q205X	nonsense	1	Pathogenic	0.000000
208.	c.1351+1G>A		essential splice site	1	Pathogenic	0.000000
209.	c.3332_3335dupAGTG	p.W1112X	nonsense	1	Pathogenic	0.000000
210.	c.1841A>G	p.Y614C	missense	1	VUS favour pathogenic	0.000000
211.	c.2780_2781delCA		frameshift	1	Pathogenic	0.000000
212.	c.1273C>T	p.Q425X	nonsense	1	Pathogenic	0.000000
213.	c.2953A>T	p.K985X	nonsense	1	Pathogenic	0.000000
214.	c.2828G>A	p.R943Q	missense	1	VUS	0.000025
215.	c.1575T>G	p.Y525X	nonsense	1	Pathogenic	0.000000
216.	c.2939G>A	p.R980H	missense	1	VUS	0.000000
217.	c.2308+1G>A		essential splice site	1	Pathogenic	0.000000
218.	c.1535T>A	p.L512Q	missense	1	VUS favour pathogenic	0.000000
219.	c.104G>A	p.R35Q	missense	1	VUS	0.000079
220.	c.3815-1G>A		essential splice site	1	Pathogenic	0.000000
221.	c.451G>A	p.D151N	missense	1	VUS	0.000041
222.	c.3335G>A	p.W1112X	nonsense	1	Pathogenic	0.000000
223.	c.2993A>G	p.Q998R	missense	1	VUS favour pathogenic	0.000000
224.	c.3735delC		frameshift	1	Likely Pathogenic	0.000000
225.	c.3065G>C	p.R1022P	missense	1	VUS favour pathogenic	0.000025
226.	c.1591G>C	p.G531R	missense	1	VUS favour pathogenic	0.000017
227.	c.1950C>G	p.D650E	missense	1	VUS	0.000000
228.	c.2525A>G	p.Y842C	missense	1	VUS	0.000000
229.	c.566T>A	p.V189D	missense	1	VUS	0.000000
230.	c.932C>T	p.S311L	missense	1	VUS	0.000000
231.	c.1693A>T	p.K565X	nonsense	1	Pathogenic	0.000000
232.	c.3181C>T	p.Q1061X	nonsense	1	Pathogenic	0.000016
233.	c.2197C>T	p.R733C	missense	1	VUS	0.000085
234.	c.223G>A	p.D75N	missense	1	VUS favour pathogenic	0.000091
235.	c.2737+1G>C		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.