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