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