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