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.2308G>A	p.D770N	missense	6	Likely Pathogenic	0.000008
16.	c.1505G>A	p.R502Q	missense	6	Pathogenic	0.000000
17.	c.2864_2865delCT		frameshift	6	Pathogenic	0.000000
18.	c.3226_3227insT		frameshift	6	Pathogenic	0.000000
19.	c.913_914delTT		frameshift	5	Pathogenic	0.000000
20.	c.2374T>C	p.W792R	missense	5	Likely Pathogenic	0.000000
21.	c.3742_3759dup	p.Gly1248_Cys1253dup	inframe	4	Likely Pathogenic	0.000000
22.	c.2573G>A	p.S858N	missense	4	VUS favour pathogenic	0.000000
23.	c.2096delC		frameshift	4	Pathogenic	0.000000
24.	c.26-2A>G		essential splice site	4	Pathogenic	0.000051
25.	c.2182G>T	p.E728X	nonsense	4	Pathogenic	0.000000
26.	c.821+1G>A		essential splice site	4	Pathogenic	0.000043
27.	c.1483C>G	p.R495G	missense	4	Likely Pathogenic	0.000000
28.	c.2905+1G>A		essential splice site	4	Pathogenic	0.000000
29.	c.2454G>A	p.W818X	nonsense	4	Pathogenic	0.000000
30.	c.3064C>T	p.R1022C	missense	4	VUS favour pathogenic	0.000008
31.	c.710A>C	p.Y237S	missense	3	Likely Pathogenic	0.000000
32.	c.2450G>A	p.R817Q	missense	3	VUS favour pathogenic	0.000016
33.	c.2311_2312insG	p.Val771GlyfsX62	frameshift	3	Pathogenic	0.000000
34.	c.3767_3769delCCA	p.Thr1256del	inframe	3	Likely Pathogenic	0.000000
35.	c.3190+1G>A		essential splice site	3	Pathogenic	0.000000
36.	c.1828G>A	p.D610N	missense	3	VUS	0.000000
37.	c.3233G>A	p.W1078X	nonsense	3	Pathogenic	0.000022
38.	c.2920C>T	p.Q974X	nonsense	3	Pathogenic	0.000000
39.	c.2873C>T	p.T958I	missense	3	VUS favour benign	0.000065
40.	c.355G>A	p.E119K	missense	3	VUS	0.000000
41.	c.1591G>A	p.G531R	missense	3	VUS favour pathogenic	0.000017
42.	c.3491-2A>T		essential splice site	3	Pathogenic	0.000000
43.	c.2905C>T	p.Q969X	nonsense	3	Pathogenic	0.000000
44.	c.1790G>A	p.R597Q	missense	2	VUS favour pathogenic	0.000000
45.	c.1483C>T	p.R495W	missense	2	VUS favour pathogenic	0.000000
46.	c.1863delC	p.Phe621LeufsX42	frameshift	2	Pathogenic	0.000000
47.	c.2943_2947delGACCA		frameshift	2	Pathogenic	0.000000
48.	c.1766G>A	p.R589H	missense	2	VUS	0.000000
49.	c.927-2A>G		essential splice site	2	Pathogenic	0.000000
50.	c.2558delG		frameshift	2	Pathogenic	0.000000
51.	c.3192_3193insC	p.Lys1065GlnfsX12	frameshift	2	Pathogenic	0.000000
52.	c.2882C>T	p.P961L	missense	2	VUS	0.000048
53.	c.3624_3625insC	p.Lys1209GlnfsX33	frameshift	2	Pathogenic	0.000000
54.	c.999C>G	p.Y333X	nonsense	2	Pathogenic	0.000000
55.	c.1210C>T	p.Q404X	nonsense	2	Pathogenic	0.000000
56.	c.532G>A	p.V178M	missense	2	VUS favour pathogenic	0.000020
57.	c.3190+2T>G		essential splice site	2	Pathogenic	0.000016
58.	c.1869C>A	p.C623X	nonsense	2	Pathogenic	0.000000
59.	c.3624delC		frameshift	2	Pathogenic	0.000000
60.	c.1895delT	p.Met632ArgfsX31	frameshift	2	Pathogenic	0.000000
61.	c.814C>T	p.R272C	missense	2	VUS	0.000083
62.	c.1037G>A	p.R346H	missense	2	VUS	0.000000
63.	c.1513_1515delAAG		inframe	2	VUS favour pathogenic	0.000000
64.	c.636C>G	p.S212R	missense	2	VUS favour pathogenic	0.000000
65.	c.772+1G>A		essential splice site	2	Pathogenic	0.000000
66.	c.2604_2605delinsA	p.S871fs	frameshift	2	Pathogenic	0.000000
67.	c.1828G>C	p.D610H	missense	2	VUS favour benign	0.000058
68.	c.436_437insA	p.Thr146AsnfsX7	frameshift	2	Pathogenic	0.000000
69.	c.1934C>T	p.P645L	missense	2	VUS	0.000000
70.	c.3627+1G>A		essential splice site	2	Pathogenic	0.000000
71.	c.1357_1358delCC		frameshift	2	Pathogenic	0.000000
72.	c.2320G>A	p.A774T	missense	2	VUS	0.000000
73.	c.1897+1G>A		essential splice site	2	Pathogenic	0.000000
74.	c.2170C>T	p.R724W	missense	1	VUS	0.000019
75.	c.3676C>T	p.R1226C	missense	1	VUS	0.000058
76.	c.3049G>A	p.E1017K	missense	1	VUS favour benign	0.000085
77.	c.3288delG		frameshift	1	Pathogenic	0.000000
78.	c.2938C>T	p.R980C	missense	1	VUS	0.000062
79.	c.1294G>A	p.A432T	missense	1	VUS	0.000037
80.	c.3G>C	p.Met1?	missense	1	Likely Pathogenic	0.000000
81.	c.2557G>A	p.G853S	missense	1	VUS	0.000008
82.	c.1156G>T	p.E386X	nonsense	1	Pathogenic	0.000000
83.	c.1628delA		frameshift	1	Pathogenic	0.000000
84.	c.3040delC	p.Leu1014TrpfsX6	frameshift	1	Pathogenic	0.000000
85.	c.1090+1G>A		essential splice site	1	Pathogenic	0.000000
86.	c.2737+2T>A		essential splice site	1	Pathogenic	0.000000
87.	c.3605G>A	p.C1202Y	missense	1	Likely Pathogenic	0.000000
88.	c.2953A>T	p.K985X	nonsense	1	Pathogenic	0.000000
89.	c.613C>T	p.Q205X	nonsense	1	Pathogenic	0.000000
90.	c.1778C>T	p.S593F	missense	1	VUS favour pathogenic	0.000034
91.	c.3332_3335dupAGTG	p.W1112X	nonsense	1	Pathogenic	0.000000
92.	c.1841A>G	p.Y614C	missense	1	VUS favour pathogenic	0.000000
93.	c.2449C>T	p.R817W	missense	1	VUS	0.000000
94.	c.2312T>C	p.V771A	missense	1	VUS	0.000000
95.	c.2939G>A	p.R980H	missense	1	VUS	0.000000
96.	c.1535T>A	p.L512Q	missense	1	VUS favour pathogenic	0.000000
97.	c.3815-1G>A		essential splice site	1	Pathogenic	0.000000
98.	c.518C>A	p.T173N	missense	1	VUS	0.000000
99.	c.1950C>G	p.D650E	missense	1	VUS	0.000000
100.	c.1693A>T	p.K565X	nonsense	1	Pathogenic	0.000000
101.	c.2654C>T	p.T885M	missense	1	VUS	0.000022
102.	c.3065G>C	p.R1022P	missense	1	VUS favour pathogenic	0.000025
103.	c.844C>T	p.R282W	missense	1	VUS favour pathogenic	0.000000
104.	c.3791G>A	p.C1264Y	missense	1	VUS	0.000008
105.	c.2737+1G>C		essential splice site	1	Pathogenic	0.000000
106.	c.3277G>T	p.G1093C	missense	1	VUS	0.000020
107.	c.1591G>C	p.G531R	missense	1	VUS favour pathogenic	0.000017
108.	c.1575T>G	p.Y525X	nonsense	1	Pathogenic	0.000000
109.	c.1038_1042dupCGGCA		frameshift	1	Pathogenic	0.000008
110.	c.3735delC		frameshift	1	Likely Pathogenic	0.000000
111.	c.1678delG	p.Asp560ThrfsX19	frameshift	1	Pathogenic	0.000000
112.	c.2490_2491insT	p.His831SerfsTer2	frameshift	1	Pathogenic	0.000024
113.	c.2556_2557delinsTCT	p.Gly853fs	frameshift	1	Pathogenic	0.000000
114.	c.1224-2A>G		essential splice site	1	Pathogenic	0.000000
115.	c.2149-1G>A		essential splice site	1	Pathogenic	0.000000
116.	c.821+1G>C		essential splice site	1	Pathogenic	0.000000
117.	c.3408C>A	p.Y1136X	nonsense	1	Pathogenic	0.000000
118.	c.459delC		frameshift	1	Pathogenic	0.000000
119.	c.333_334insT	p.E112X	nonsense	1	Pathogenic	0.000000
120.	c.2906-2A>G		essential splice site	1	Pathogenic	0.000000
121.	c.3763G>A	p.A1255T	missense	1	VUS favour pathogenic	0.000075
122.	c.533delT	p.Val178GlyfsX7	frameshift	1	Pathogenic	0.000000
123.	c.2524_2525insT	p.Tyr842LeufsX42	frameshift	1	Pathogenic	0.000000
124.	c.932C>T	p.S311L	missense	1	VUS	0.000000
125.	c.2610_2611insC	p.Ser871GlnfsX13	frameshift	1	Pathogenic	0.000000
126.	c.2197C>T	p.R733C	missense	1	VUS	0.000085
127.	c.3065G>A	p.R1022H	missense	1	VUS favour pathogenic	0.000000
128.	c.2269G>A	p.V757M	missense	1	VUS	0.000066
129.	c.833delG	p.Gly278GlufsX22	frameshift	1	Pathogenic	0.000000
130.	c.1960C>T	p.R654C	missense	1	VUS favour benign	0.000008
131.	c.1418T>C	p.F473S	missense	1	VUS	0.000000
132.	c.2308+1G>T		essential splice site	1	Pathogenic	0.000000
133.	c.853G>A	p.D285N	missense	1	VUS	0.000000
134.	c.3694A>T	p.K1232X	nonsense	1	Pathogenic	0.000000
135.	c.3281A>T	p.N1094I	missense	1	VUS	0.000000
136.	c.1168delC		frameshift	1	Pathogenic	0.000000
137.	c.1672G>A	p.A558T	missense	1	VUS	0.000008
138.	c.2833_2834delCG		frameshift	1	Pathogenic	0.000000
139.	c.1624+2T>C		essential splice site	1	Pathogenic	0.000000
140.	c.2518G>A	p.V840M	missense	1	VUS	0.000016
141.	c.3413G>C	p.R1138P	missense	1	VUS	0.000000
142.	c.3415G>A	p.V1139I	missense	1	VUS	0.000087
143.	c.2210C>T	p.T737M	missense	1	VUS	0.000050
144.	c.373G>T	p.A125S	missense	1	VUS	0.000000
145.	c.3083C>G	p.T1028S	missense	1	VUS	0.000000
146.	c.1699_1700delGA	p.Glu567GlyfsX4	frameshift	1	Pathogenic	0.000000
147.	c.1999_2000delinsG	p.Leu667AspfsX15	frameshift	1	Pathogenic	0.000000
148.	c.932C>A	p.S311X	nonsense	1	Pathogenic	0.000000
149.	c.1343T>C	p.F448S	missense	1	Likely Pathogenic	0.000000
150.	c.1000G>T	p.E334X	nonsense	1	Pathogenic	0.000000
151.	c.2723A>G	p.Y908C	missense	1	VUS	0.000062
152.	c.1924C>T	p.Q642X	nonsense	1	Pathogenic	0.000000
153.	c.2747G>A	p.W916X	nonsense	1	Pathogenic	0.000000
154.	c.2394_2395insT	p.Gly799TrpfsX34	frameshift	1	Pathogenic	0.000000
155.	c.3166_3167insG	p.Ala1056GlyfsX9	frameshift	1	Pathogenic	0.000000
156.	c.2533C>T	p.R845C	missense	1	VUS favour pathogenic	0.000000
157.	c.2965G>T	p.E989X	nonsense	1	Pathogenic	0.000000
158.	c.3181C>T	p.Q1061X	nonsense	1	Pathogenic	0.000016
159.	c.821+2T>C		essential splice site	1	Pathogenic	0.000000
160.	c.2163delC	p.Glu722ArgfsX32	frameshift	1	Pathogenic	0.000000
161.	c.223G>A	p.D75N	missense	1	VUS favour pathogenic	0.000091
162.	c.3476_3479dupTTAT	p.Pro1161TyrfsX9	frameshift	1	Pathogenic	0.000000
163.	c.2525A>G	p.Y842C	missense	1	VUS	0.000000
164.	c.2013_2016delinsGG	p.Pro672AspfsX20	frameshift	1	Pathogenic	0.000000
165.	c.713G>A	p.R238H	missense	1	VUS	0.000074
166.	c.2459G>A	p.R820Q	missense	1	Likely Pathogenic	0.000016
167.	c.431_432delGT	p.Gly144AlafsX8	frameshift	1	Pathogenic	0.000000
168.	c.1800delA		frameshift	1	Pathogenic	0.000000
169.	c.566T>A	p.V189D	missense	1	VUS	0.000000
170.	c.1397T>A	p.M466K	missense	1	VUS	0.000008
171.	c.2436G>T	p.K812N	missense	1	VUS	0.000000
172.	c.2828G>A	p.R943Q	missense	1	VUS	0.000025
173.	c.1273C>T	p.Q425X	nonsense	1	Pathogenic	0.000000
174.	c.1456T>G	p.W486G	missense	1	Likely Pathogenic	0.000000
175.	c.3825A>G	p.X1275TrpextX77	nonsense	1	Likely Pathogenic	0.000000
176.	c.451G>A	p.D151N	missense	1	VUS	0.000041
177.	c.1090+1G>T		essential splice site	1	Pathogenic	0.000000
178.	c.104G>A	p.R35Q	missense	1	VUS	0.000079
179.	c.3476_3477delTT		frameshift	1	Pathogenic	0.000000
180.	c.3797G>A	p.C1266Y	missense	1	Likely Pathogenic	0.000000
181.	c.177_187del	p.Glu60AlafsX49	frameshift	1	Pathogenic	0.000000
182.	c.2780_2781delCA		frameshift	1	Pathogenic	0.000000
183.	c.1458-1G>A		essential splice site	1	Pathogenic	0.000000
184.	c.1351+1G>A		essential splice site	1	Pathogenic	0.000000
185.	c.551_552insT	p.Lys185GlufsX56	frameshift	1	Pathogenic	0.000000
186.	c.2541C>A	p.Y847X	nonsense	1	Pathogenic	0.000000
187.	c.2234A>G	p.D745G	missense	1	VUS	0.000000
188.	c.1021G>A	p.G341S	missense	1	VUS favour pathogenic	0.000025
189.	c.3331-1G>A		essential splice site	1	Pathogenic	0.000000
190.	c.3580G>A	p.A1194T	missense	1	VUS	0.000008
191.	c.1586C>G	p.T529S	missense	1	VUS favour pathogenic	0.000000
192.	c.3335G>A	p.W1112X	nonsense	1	Pathogenic	0.000000
193.	c.481C>A	p.P161T	missense	1	VUS favour pathogenic	0.000041
194.	c.966G>A	p.W322X	nonsense	1	Pathogenic	0.000000
195.	c.1505G>T	p.R502L	missense	1	VUS favour pathogenic	0.000000
196.	c.3548T>G	p.F1183C	missense	1	Likely Pathogenic	0.000000
197.	c.1358C>T	p.P453L	missense	1	VUS	0.000008
198.	c.2308+1G>A		essential splice site	1	Pathogenic	0.000000
199.	c.2517_2538del	p.Val840ThrfsX32	frameshift	1	Pathogenic	0.000000
200.	c.2560A>G	p.M854V	missense	1	VUS	0.000000
201.	c.3811C>T	p.R1271X	nonsense	1	Pathogenic	0.000025
202.	c.2905+1G>C		essential splice site	1	Pathogenic	0.000000
203.	c.3098G>A	p.R1033Q	missense	1	VUS	0.000000
204.	c.655-1G>A		essential splice site	1	Pathogenic	0.000000
205.	c.2993A>G	p.Q998R	missense	1	VUS favour pathogenic	0.000000
206.	c.3746G>T	p.G1249V	missense	1	VUS	0.000000
207.	c.3776delA		frameshift	1	Pathogenic	0.000000
208.	c.3068_3069insA	p.Asn1023LysfsX28	frameshift	1	Pathogenic	0.000000
209.	c.1213A>G	p.M405V	missense	1	Pathogenic	0.000000
210.	c.2113_2114insA	p.Thr705AsnfsX3	frameshift	1	Pathogenic	0.000000
211.	c.2671C>T	p.R891W	missense	1	Likely Pathogenic	0.000031
212.	c.1351+2T>C		essential splice site	1	Pathogenic	0.000000
213.	c.2641G>A	p.V881I	missense	1	VUS	0.000018
214.	c.2875_2876delAC	p.Thr959GlyfsX91	frameshift	1	Pathogenic	0.000000
215.	c.3690_3691delCA	p.Phe1230LeufsX11	frameshift	1	Pathogenic	0.000000
216.	c.1892delT		frameshift	1	Pathogenic	0.000000
217.	c.2437A>T	p.K813X	nonsense	1	Pathogenic	0.000000
218.	c.3753T>G	p.Y1251X	nonsense	1	Pathogenic	0.000000
219.	c.3253G>T	p.E1085X	nonsense	1	Pathogenic	0.000000
220.	c.2528_2536delAGATGCGCG	p.Glu843_Arg845del	inframe	1	Pathogenic	0.000000
221.	c.290C>T	p.A97V	missense	1	VUS favour pathogenic	0.000000
222.	c.993_994insT	p.E332X	nonsense	1	Pathogenic	0.000000
223.	c.3742G>A	p.G1248R	missense	1	VUS	0.000033
224.	c.3373G>A	p.V1125M	missense	1	VUS favour pathogenic	0.000022
225.	c.436A>C	p.T146P	missense	1	VUS	0.000000
226.	c.506-1G>T		essential splice site	1	Pathogenic	0.000000
227.	c.326C>T	p.A109V	missense	1	VUS	0.000000
228.	c.2040_2041insT	p.Val681CysfsX12	frameshift	1	Pathogenic	0.000000
229.	c.103C>T	p.R35W	missense	1	VUS	0.000056
230.	c.1188G>T	p.W396C	missense	1	VUS	0.000000
231.	c.2534_2538delGCGTC		frameshift	1	Pathogenic	0.000000
232.	c.2048G>A	p.W683X	nonsense	1	Pathogenic	0.000000
233.	c.931T>A	p.S311T	missense	1	VUS	0.000000
234.	c.3286G>T	p.E1096X	nonsense	1	Pathogenic	0.000000
235.	c.1540A>G	p.I514V	missense	1	VUS	0.000008
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.