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