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