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