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.3G>C	p.Met1?	missense	1	Likely Pathogenic	0.000000
2.	c.26-2A>G		essential splice site	4	Pathogenic	0.000051
3.	c.103C>T	p.R35W	missense	1	VUS	0.000056
4.	c.104G>A	p.R35Q	missense	1	VUS	0.000079
5.	c.177_187del	p.Glu60AlafsX49	frameshift	1	Pathogenic	0.000000
6.	c.223G>A	p.D75N	missense	1	VUS favour pathogenic	0.000091
7.	c.290C>T	p.A97V	missense	1	VUS favour pathogenic	0.000000
8.	c.326C>T	p.A109V	missense	1	VUS	0.000000
9.	c.333_334insT	p.E112X	nonsense	1	Pathogenic	0.000000
10.	c.355G>A	p.E119K	missense	3	VUS	0.000000
11.	c.373G>T	p.A125S	missense	1	VUS	0.000000
12.	c.431_432delGT	p.Gly144AlafsX8	frameshift	1	Pathogenic	0.000000
13.	c.436_437insA	p.Thr146AsnfsX7	frameshift	2	Pathogenic	0.000000
14.	c.436A>C	p.T146P	missense	1	VUS	0.000000
15.	c.442G>A	p.G148R	missense	7	VUS favour pathogenic	0.000042
16.	c.451G>A	p.D151N	missense	1	VUS	0.000041
17.	c.459delC		frameshift	1	Pathogenic	0.000000
18.	c.481C>A	p.P161T	missense	1	VUS favour pathogenic	0.000041
19.	c.506-1G>T		essential splice site	1	Pathogenic	0.000000
20.	c.518C>A	p.T173N	missense	1	VUS	0.000000
21.	c.532G>A	p.V178M	missense	2	VUS favour pathogenic	0.000020
22.	c.533delT	p.Val178GlyfsX7	frameshift	1	Pathogenic	0.000000
23.	c.551_552insT	p.Lys185GlufsX56	frameshift	1	Pathogenic	0.000000
24.	c.566T>A	p.V189D	missense	1	VUS	0.000000
25.	c.613C>T	p.Q205X	nonsense	1	Pathogenic	0.000000
26.	c.636C>G	p.S212R	missense	2	VUS favour pathogenic	0.000000
27.	c.655-1G>A		essential splice site	1	Pathogenic	0.000000
28.	c.655G>C	p.V219L	missense	8	Likely Pathogenic	0.000000
29.	c.710A>C	p.Y237S	missense	3	Likely Pathogenic	0.000000
30.	c.713G>A	p.R238H	missense	1	VUS	0.000074
31.	c.772G>A	p.E258K	missense	21	Pathogenic	0.000039
32.	c.772+1G>A		essential splice site	2	Pathogenic	0.000000
33.	c.814C>T	p.R272C	missense	2	VUS	0.000083
34.	c.821+1G>A		essential splice site	4	Pathogenic	0.000043
35.	c.821+1G>C		essential splice site	1	Pathogenic	0.000000
36.	c.821+2T>C		essential splice site	1	Pathogenic	0.000000
37.	c.833delG	p.Gly278GlufsX22	frameshift	1	Pathogenic	0.000000
38.	c.844C>T	p.R282W	missense	1	VUS favour pathogenic	0.000000
39.	c.853G>A	p.D285N	missense	1	VUS	0.000000
40.	c.913_914delTT		frameshift	5	Pathogenic	0.000000
41.	c.927-2A>G		essential splice site	2	Pathogenic	0.000000
42.	c.931T>A	p.S311T	missense	1	VUS	0.000000
43.	c.932C>A	p.S311X	nonsense	1	Pathogenic	0.000000
44.	c.932C>T	p.S311L	missense	1	VUS	0.000000
45.	c.966G>A	p.W322X	nonsense	1	Pathogenic	0.000000
46.	c.993_994insT	p.E332X	nonsense	1	Pathogenic	0.000000
47.	c.999C>G	p.Y333X	nonsense	2	Pathogenic	0.000000
48.	c.1000G>T	p.E334X	nonsense	1	Pathogenic	0.000000
49.	c.1021G>A	p.G341S	missense	1	VUS favour pathogenic	0.000025
50.	c.1037G>A	p.R346H	missense	2	VUS	0.000000
51.	c.1038_1042dupCGGCA		frameshift	1	Pathogenic	0.000008
52.	c.1090+1G>T		essential splice site	1	Pathogenic	0.000000
53.	c.1090+1G>A		essential splice site	1	Pathogenic	0.000000
54.	c.1156G>T	p.E386X	nonsense	1	Pathogenic	0.000000
55.	c.1168delC		frameshift	1	Pathogenic	0.000000
56.	c.1188G>T	p.W396C	missense	1	VUS	0.000000
57.	c.1210C>T	p.Q404X	nonsense	2	Pathogenic	0.000000
58.	c.1213A>G	p.M405V	missense	1	Pathogenic	0.000000
59.	c.1224-2A>G		essential splice site	1	Pathogenic	0.000000
60.	c.1273C>T	p.Q425X	nonsense	1	Pathogenic	0.000000
61.	c.1294G>A	p.A432T	missense	1	VUS	0.000037
62.	c.1343T>C	p.F448S	missense	1	Likely Pathogenic	0.000000
63.	c.1351+1G>A		essential splice site	1	Pathogenic	0.000000
64.	c.1351+2T>C		essential splice site	1	Pathogenic	0.000000
65.	c.1357_1358delCC		frameshift	2	Pathogenic	0.000000
66.	c.1358C>T	p.P453L	missense	1	VUS	0.000008
67.	c.1397T>A	p.M466K	missense	1	VUS	0.000008
68.	c.1418T>C	p.F473S	missense	1	VUS	0.000000
69.	c.1456T>G	p.W486G	missense	1	Likely Pathogenic	0.000000
70.	c.1458-1G>A		essential splice site	1	Pathogenic	0.000000
71.	c.1483C>G	p.R495G	missense	4	Likely Pathogenic	0.000000
72.	c.1483C>T	p.R495W	missense	2	VUS favour pathogenic	0.000000
73.	c.1484G>A	p.R495Q	missense	10	VUS favour pathogenic	0.000008
74.	c.1504C>T	p.R502W	missense	45	Pathogenic	0.000024
75.	c.1505G>T	p.R502L	missense	1	VUS favour pathogenic	0.000000
76.	c.1505G>A	p.R502Q	missense	6	Pathogenic	0.000000
77.	c.1513_1515delAAG		inframe	2	VUS favour pathogenic	0.000000
78.	c.1535T>A	p.L512Q	missense	1	VUS favour pathogenic	0.000000
79.	c.1540A>G	p.I514V	missense	1	VUS	0.000008
80.	c.1575T>G	p.Y525X	nonsense	1	Pathogenic	0.000000
81.	c.1586C>G	p.T529S	missense	1	VUS favour pathogenic	0.000000
82.	c.1591G>A	p.G531R	missense	3	VUS favour pathogenic	0.000017
83.	c.1591G>C	p.G531R	missense	1	VUS favour pathogenic	0.000017
84.	c.1624G>C	p.E542Q	missense	17	Likely Pathogenic	0.000024
85.	c.1624+2T>C		essential splice site	1	Pathogenic	0.000000
86.	c.1628delA		frameshift	1	Pathogenic	0.000000
87.	c.1672G>A	p.A558T	missense	1	VUS	0.000008
88.	c.1678delG	p.Asp560ThrfsX19	frameshift	1	Pathogenic	0.000000
89.	c.1693A>T	p.K565X	nonsense	1	Pathogenic	0.000000
90.	c.1699_1700delGA	p.Glu567GlyfsX4	frameshift	1	Pathogenic	0.000000
91.	c.1766G>A	p.R589H	missense	2	VUS	0.000000
92.	c.1778C>T	p.S593F	missense	1	VUS favour pathogenic	0.000034
93.	c.1790G>A	p.R597Q	missense	2	VUS favour pathogenic	0.000000
94.	c.1800delA		frameshift	1	Pathogenic	0.000000
95.	c.1828G>C	p.D610H	missense	2	VUS favour benign	0.000058
96.	c.1828G>A	p.D610N	missense	3	VUS	0.000000
97.	c.1841A>G	p.Y614C	missense	1	VUS favour pathogenic	0.000000
98.	c.1863delC	p.Phe621LeufsX42	frameshift	2	Pathogenic	0.000000
99.	c.1869C>A	p.C623X	nonsense	2	Pathogenic	0.000000
100.	c.1892delT		frameshift	1	Pathogenic	0.000000
101.	c.1895delT	p.Met632ArgfsX31	frameshift	2	Pathogenic	0.000000
102.	c.1897+1G>A		essential splice site	2	Pathogenic	0.000000
103.	c.1924C>T	p.Q642X	nonsense	1	Pathogenic	0.000000
104.	c.1928-2A>G		essential splice site	20	Pathogenic	0.000000
105.	c.1934C>T	p.P645L	missense	2	VUS	0.000000
106.	c.1950C>G	p.D650E	missense	1	VUS	0.000000
107.	c.1960C>T	p.R654C	missense	1	VUS favour benign	0.000008
108.	c.1999_2000delinsG	p.Leu667AspfsX15	frameshift	1	Pathogenic	0.000000
109.	c.2013_2016delinsGG	p.Pro672AspfsX20	frameshift	1	Pathogenic	0.000000
110.	c.2040_2041insT	p.Val681CysfsX12	frameshift	1	Pathogenic	0.000000
111.	c.2048G>A	p.W683X	nonsense	1	Pathogenic	0.000000
112.	c.2096delC		frameshift	4	Pathogenic	0.000000
113.	c.2113_2114insA	p.Thr705AsnfsX3	frameshift	1	Pathogenic	0.000000
114.	c.2149-1G>A		essential splice site	1	Pathogenic	0.000000
115.	c.2163delC	p.Glu722ArgfsX32	frameshift	1	Pathogenic	0.000000
116.	c.2170C>T	p.R724W	missense	1	VUS	0.000019
117.	c.2182G>T	p.E728X	nonsense	4	Pathogenic	0.000000
118.	c.2197C>T	p.R733C	missense	1	VUS	0.000085
119.	c.2210C>T	p.T737M	missense	1	VUS	0.000050
120.	c.2234A>G	p.D745G	missense	1	VUS	0.000000
121.	c.2269G>A	p.V757M	missense	1	VUS	0.000066
122.	c.2308G>A	p.D770N	missense	6	Likely Pathogenic	0.000008
123.	c.2308+1G>A		essential splice site	1	Pathogenic	0.000000
124.	c.2308+1G>T		essential splice site	1	Pathogenic	0.000000
125.	c.2309-2A>G		essential splice site	9	Pathogenic	0.000000
126.	c.2311_2312insG	p.Val771GlyfsX62	frameshift	3	Pathogenic	0.000000
127.	c.2312T>C	p.V771A	missense	1	VUS	0.000000
128.	c.2320G>A	p.A774T	missense	2	VUS	0.000000
129.	c.2373_2374insG	p.Trp792ValfsTer41	frameshift	26	Pathogenic	0.000037
130.	c.2374T>C	p.W792R	missense	5	Likely Pathogenic	0.000000
131.	c.2394_2395insT	p.Gly799TrpfsX34	frameshift	1	Pathogenic	0.000000
132.	c.2429G>A	p.R810H	missense	8	VUS favour pathogenic	0.000033
133.	c.2436G>T	p.K812N	missense	1	VUS	0.000000
134.	c.2437A>T	p.K813X	nonsense	1	Pathogenic	0.000000
135.	c.2449C>T	p.R817W	missense	1	VUS	0.000000
136.	c.2450G>A	p.R817Q	missense	3	VUS favour pathogenic	0.000016
137.	c.2454G>A	p.W818X	nonsense	4	Pathogenic	0.000000
138.	c.2459G>A	p.R820Q	missense	1	Likely Pathogenic	0.000016
139.	c.2490_2491insT	p.His831SerfsTer2	frameshift	1	Pathogenic	0.000024
140.	c.2517_2538del	p.Val840ThrfsX32	frameshift	1	Pathogenic	0.000000
141.	c.2518G>A	p.V840M	missense	1	VUS	0.000016
142.	c.2524_2525insT	p.Tyr842LeufsX42	frameshift	1	Pathogenic	0.000000
143.	c.2525A>G	p.Y842C	missense	1	VUS	0.000000
144.	c.2528_2536delAGATGCGCG	p.Glu843_Arg845del	inframe	1	Pathogenic	0.000000
145.	c.2533C>T	p.R845C	missense	1	VUS favour pathogenic	0.000000
146.	c.2534_2538delGCGTC		frameshift	1	Pathogenic	0.000000
147.	c.2541C>A	p.Y847X	nonsense	1	Pathogenic	0.000000
148.	c.2556_2557delinsTCT	p.Gly853fs	frameshift	1	Pathogenic	0.000000
149.	c.2557G>A	p.G853S	missense	1	VUS	0.000008
150.	c.2558delG		frameshift	2	Pathogenic	0.000000
151.	c.2560A>G	p.M854V	missense	1	VUS	0.000000
152.	c.2573G>A	p.S858N	missense	4	VUS favour pathogenic	0.000000
153.	c.2604_2605delinsA	p.S871fs	frameshift	2	Pathogenic	0.000000
154.	c.2610_2611insC	p.Ser871GlnfsX13	frameshift	1	Pathogenic	0.000000
155.	c.2641G>A	p.V881I	missense	1	VUS	0.000018
156.	c.2654C>T	p.T885M	missense	1	VUS	0.000022
157.	c.2670G>A	p.W890X	nonsense	7	Pathogenic	0.000000
158.	c.2671C>T	p.R891W	missense	1	Likely Pathogenic	0.000031
159.	c.2723A>G	p.Y908C	missense	1	VUS	0.000062
160.	c.2737+1G>C		essential splice site	1	Pathogenic	0.000000
161.	c.2737+2T>A		essential splice site	1	Pathogenic	0.000000
162.	c.2747G>A	p.W916X	nonsense	1	Pathogenic	0.000000
163.	c.2780_2781delCA		frameshift	1	Pathogenic	0.000000
164.	c.2827C>T	p.R943X	nonsense	7	Pathogenic	0.000017
165.	c.2828G>A	p.R943Q	missense	1	VUS	0.000025
166.	c.2833_2834delCG		frameshift	1	Pathogenic	0.000000
167.	c.2864_2865delCT		frameshift	6	Pathogenic	0.000000
168.	c.2873C>T	p.T958I	missense	3	VUS favour benign	0.000065
169.	c.2875_2876delAC	p.Thr959GlyfsX91	frameshift	1	Pathogenic	0.000000
170.	c.2882C>T	p.P961L	missense	2	VUS	0.000048
171.	c.2905C>T	p.Q969X	nonsense	3	Pathogenic	0.000000
172.	c.2905+1G>C		essential splice site	1	Pathogenic	0.000000
173.	c.2905+1G>A		essential splice site	4	Pathogenic	0.000000
174.	c.2906-2A>G		essential splice site	1	Pathogenic	0.000000
175.	c.2920C>T	p.Q974X	nonsense	3	Pathogenic	0.000000
176.	c.2938C>T	p.R980C	missense	1	VUS	0.000062
177.	c.2939G>A	p.R980H	missense	1	VUS	0.000000
178.	c.2943_2947delGACCA		frameshift	2	Pathogenic	0.000000
179.	c.2953A>T	p.K985X	nonsense	1	Pathogenic	0.000000
180.	c.2965G>T	p.E989X	nonsense	1	Pathogenic	0.000000
181.	c.2993A>G	p.Q998R	missense	1	VUS favour pathogenic	0.000000
182.	c.3040delC	p.Leu1014TrpfsX6	frameshift	1	Pathogenic	0.000000
183.	c.3049G>A	p.E1017K	missense	1	VUS favour benign	0.000085
184.	c.3064C>T	p.R1022C	missense	4	VUS favour pathogenic	0.000008
185.	c.3065G>A	p.R1022H	missense	1	VUS favour pathogenic	0.000000
186.	c.3065G>C	p.R1022P	missense	1	VUS favour pathogenic	0.000025
187.	c.3068_3069insA	p.Asn1023LysfsX28	frameshift	1	Pathogenic	0.000000
188.	c.3083C>G	p.T1028S	missense	1	VUS	0.000000
189.	c.3098G>A	p.R1033Q	missense	1	VUS	0.000000
190.	c.3166_3167insG	p.Ala1056GlyfsX9	frameshift	1	Pathogenic	0.000000
191.	c.3181C>T	p.Q1061X	nonsense	1	Pathogenic	0.000016
192.	c.3190+1G>A		essential splice site	3	Pathogenic	0.000000
193.	c.3190+2T>G		essential splice site	2	Pathogenic	0.000016
194.	c.3192_3193insC	p.Lys1065GlnfsX12	frameshift	2	Pathogenic	0.000000
195.	c.3226_3227insT		frameshift	6	Pathogenic	0.000000
196.	c.3233G>A	p.W1078X	nonsense	3	Pathogenic	0.000022
197.	c.3253G>T	p.E1085X	nonsense	1	Pathogenic	0.000000
198.	c.3277G>T	p.G1093C	missense	1	VUS	0.000020
199.	c.3281A>T	p.N1094I	missense	1	VUS	0.000000
200.	c.3286G>T	p.E1096X	nonsense	1	Pathogenic	0.000000
201.	c.3288delG		frameshift	1	Pathogenic	0.000000
202.	c.3330+2T>G		essential splice site	11	Pathogenic	0.000000
203.	c.3331-1G>A		essential splice site	1	Pathogenic	0.000000
204.	c.3332_3335dupAGTG	p.W1112X	nonsense	1	Pathogenic	0.000000
205.	c.3335G>A	p.W1112X	nonsense	1	Pathogenic	0.000000
206.	c.3373G>A	p.V1125M	missense	1	VUS favour pathogenic	0.000022
207.	c.3408C>A	p.Y1136X	nonsense	1	Pathogenic	0.000000
208.	c.3413G>C	p.R1138P	missense	1	VUS	0.000000
209.	c.3415G>A	p.V1139I	missense	1	VUS	0.000087
210.	c.3476_3477delTT		frameshift	1	Pathogenic	0.000000
211.	c.3476_3479dupTTAT	p.Pro1161TyrfsX9	frameshift	1	Pathogenic	0.000000
212.	c.3491-2A>T		essential splice site	3	Pathogenic	0.000000
213.	c.3548T>G	p.F1183C	missense	1	Likely Pathogenic	0.000000
214.	c.3580G>A	p.A1194T	missense	1	VUS	0.000008
215.	c.3600_3609delCTGCTGTGCT		frameshift	0	Pathogenic	0.000000
216.	c.3605G>A	p.C1202Y	missense	1	Likely Pathogenic	0.000000
217.	c.3624delC		frameshift	2	Pathogenic	0.000000
218.	c.3624_3625insC	p.Lys1209GlnfsX33	frameshift	2	Pathogenic	0.000000
219.	c.3627+1G>A		essential splice site	2	Pathogenic	0.000000
220.	c.3676C>T	p.R1226C	missense	1	VUS	0.000058
221.	c.3690_3691delCA	p.Phe1230LeufsX11	frameshift	1	Pathogenic	0.000000
222.	c.3694A>T	p.K1232X	nonsense	1	Pathogenic	0.000000
223.	c.3697C>T	p.Q1233X	nonsense	9	Pathogenic	0.000008
224.	c.3735delC		frameshift	1	Likely Pathogenic	0.000000
225.	c.3742_3759dup	p.Gly1248_Cys1253dup	inframe	4	Likely Pathogenic	0.000000
226.	c.3742G>A	p.G1248R	missense	1	VUS	0.000033
227.	c.3746G>T	p.G1249V	missense	1	VUS	0.000000
228.	c.3753T>G	p.Y1251X	nonsense	1	Pathogenic	0.000000
229.	c.3763G>A	p.A1255T	missense	1	VUS favour pathogenic	0.000075
230.	c.3767_3769delCCA	p.Thr1256del	inframe	3	Likely Pathogenic	0.000000
231.	c.3776delA		frameshift	1	Pathogenic	0.000000
232.	c.3791G>A	p.C1264Y	missense	1	VUS	0.000008
233.	c.3797G>A	p.C1266Y	missense	1	Likely Pathogenic	0.000000
234.	c.3811C>T	p.R1271X	nonsense	1	Pathogenic	0.000025
235.	c.3815-1G>A		essential splice site	1	Pathogenic	0.000000
236.	c.3825A>G	p.X1275TrpextX77	nonsense	1	Likely 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.