MYBPC3 protein-altering 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.655G>C	p.V219L	missense	8	Likely Pathogenic	0.000000
11.	c.2429G>A	p.R810H	missense	8	VUS favour pathogenic	0.000033
12.	c.2827C>T	p.R943X	nonsense	7	Pathogenic	0.000017
13.	c.2670G>A	p.W890X	nonsense	7	Pathogenic	0.000000
14.	c.442G>A	p.G148R	missense	7	VUS favour pathogenic	0.000042
15.	c.2864_2865delCT		frameshift	6	Pathogenic	0.000000
16.	c.2308G>A	p.D770N	missense	6	Likely Pathogenic	0.000008
17.	c.3226_3227insT		frameshift	6	Pathogenic	0.000000
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.2573G>A	p.S858N	missense	4	VUS favour pathogenic	0.000000
22.	c.2096delC		frameshift	4	Pathogenic	0.000000
23.	c.26-2A>G		essential splice site	4	Pathogenic	0.000051
24.	c.821+1G>A		essential splice site	4	Pathogenic	0.000043
25.	c.1483C>G	p.R495G	missense	4	Likely Pathogenic	0.000000
26.	c.2905+1G>A		essential splice site	4	Pathogenic	0.000000
27.	c.2454G>A	p.W818X	nonsense	4	Pathogenic	0.000000
28.	c.3064C>T	p.R1022C	missense	4	VUS favour pathogenic	0.000008
29.	c.2182G>T	p.E728X	nonsense	4	Pathogenic	0.000000
30.	c.3742_3759dup	p.Gly1248_Cys1253dup	inframe	4	Likely Pathogenic	0.000000
31.	c.2311_2312insG	p.Val771GlyfsX62	frameshift	3	Pathogenic	0.000000
32.	c.1828G>A	p.D610N	missense	3	VUS	0.000000
33.	c.355G>A	p.E119K	missense	3	VUS	0.000000
34.	c.3190+1G>A		essential splice site	3	Pathogenic	0.000000
35.	c.2873C>T	p.T958I	missense	3	VUS favour benign	0.000065
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.2905C>T	p.Q969X	nonsense	3	Pathogenic	0.000000
39.	c.2920C>T	p.Q974X	nonsense	3	Pathogenic	0.000000
40.	c.710A>C	p.Y237S	missense	3	Likely Pathogenic	0.000000
41.	c.2450G>A	p.R817Q	missense	3	VUS favour pathogenic	0.000016
42.	c.3491-2A>T		essential splice site	3	Pathogenic	0.000000
43.	c.3233G>A	p.W1078X	nonsense	3	Pathogenic	0.000022
44.	c.1863delC	p.Phe621LeufsX42	frameshift	2	Pathogenic	0.000000
45.	c.1210C>T	p.Q404X	nonsense	2	Pathogenic	0.000000
46.	c.532G>A	p.V178M	missense	2	VUS favour pathogenic	0.000020
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.3190+2T>G		essential splice site	2	Pathogenic	0.000016
51.	c.1934C>T	p.P645L	missense	2	VUS	0.000000
52.	c.3192_3193insC	p.Lys1065GlnfsX12	frameshift	2	Pathogenic	0.000000
53.	c.3624_3625insC	p.Lys1209GlnfsX33	frameshift	2	Pathogenic	0.000000
54.	c.999C>G	p.Y333X	nonsense	2	Pathogenic	0.000000
55.	c.1766G>A	p.R589H	missense	2	VUS	0.000000
56.	c.1513_1515delAAG		inframe	2	VUS favour pathogenic	0.000000
57.	c.636C>G	p.S212R	missense	2	VUS favour pathogenic	0.000000
58.	c.1895delT	p.Met632ArgfsX31	frameshift	2	Pathogenic	0.000000
59.	c.3627+1G>A		essential splice site	2	Pathogenic	0.000000
60.	c.1357_1358delCC		frameshift	2	Pathogenic	0.000000
61.	c.772+1G>A		essential splice site	2	Pathogenic	0.000000
62.	c.2604_2605delinsA	p.S871fs	frameshift	2	Pathogenic	0.000000
63.	c.814C>T	p.R272C	missense	2	VUS	0.000083
64.	c.1790G>A	p.R597Q	missense	2	VUS favour pathogenic	0.000000
65.	c.1483C>T	p.R495W	missense	2	VUS favour pathogenic	0.000000
66.	c.2320G>A	p.A774T	missense	2	VUS	0.000000
67.	c.2943_2947delGACCA		frameshift	2	Pathogenic	0.000000
68.	c.1897+1G>A		essential splice site	2	Pathogenic	0.000000
69.	c.927-2A>G		essential splice site	2	Pathogenic	0.000000
70.	c.2558delG		frameshift	2	Pathogenic	0.000000
71.	c.1828G>C	p.D610H	missense	2	VUS favour benign	0.000058
72.	c.2882C>T	p.P961L	missense	2	VUS	0.000048
73.	c.1037G>A	p.R346H	missense	2	VUS	0.000000
74.	c.566T>A	p.V189D	missense	1	VUS	0.000000
75.	c.3040delC	p.Leu1014TrpfsX6	frameshift	1	Pathogenic	0.000000
76.	c.2197C>T	p.R733C	missense	1	VUS	0.000085
77.	c.2436G>T	p.K812N	missense	1	VUS	0.000000
78.	c.2737+2T>A		essential splice site	1	Pathogenic	0.000000
79.	c.3605G>A	p.C1202Y	missense	1	Likely Pathogenic	0.000000
80.	c.1960C>T	p.R654C	missense	1	VUS favour benign	0.000008
81.	c.613C>T	p.Q205X	nonsense	1	Pathogenic	0.000000
82.	c.2308+1G>T		essential splice site	1	Pathogenic	0.000000
83.	c.3332_3335dupAGTG	p.W1112X	nonsense	1	Pathogenic	0.000000
84.	c.2953A>T	p.K985X	nonsense	1	Pathogenic	0.000000
85.	c.1168delC		frameshift	1	Pathogenic	0.000000
86.	c.1535T>A	p.L512Q	missense	1	VUS favour pathogenic	0.000000
87.	c.1624+2T>C		essential splice site	1	Pathogenic	0.000000
88.	c.3742G>A	p.G1248R	missense	1	VUS	0.000033
89.	c.2654C>T	p.T885M	missense	1	VUS	0.000022
90.	c.932C>A	p.S311X	nonsense	1	Pathogenic	0.000000
91.	c.3373G>A	p.V1125M	missense	1	VUS favour pathogenic	0.000022
92.	c.1343T>C	p.F448S	missense	1	Likely Pathogenic	0.000000
93.	c.1586C>G	p.T529S	missense	1	VUS favour pathogenic	0.000000
94.	c.103C>T	p.R35W	missense	1	VUS	0.000056
95.	c.1924C>T	p.Q642X	nonsense	1	Pathogenic	0.000000
96.	c.966G>A	p.W322X	nonsense	1	Pathogenic	0.000000
97.	c.2737+1G>C		essential splice site	1	Pathogenic	0.000000
98.	c.3277G>T	p.G1093C	missense	1	VUS	0.000020
99.	c.2534_2538delGCGTC		frameshift	1	Pathogenic	0.000000
100.	c.3548T>G	p.F1183C	missense	1	Likely Pathogenic	0.000000
101.	c.3791G>A	p.C1264Y	missense	1	VUS	0.000008
102.	c.2556_2557delinsTCT	p.Gly853fs	frameshift	1	Pathogenic	0.000000
103.	c.3181C>T	p.Q1061X	nonsense	1	Pathogenic	0.000016
104.	c.2517_2538del	p.Val840ThrfsX32	frameshift	1	Pathogenic	0.000000
105.	c.2149-1G>A		essential splice site	1	Pathogenic	0.000000
106.	c.821+1G>C		essential splice site	1	Pathogenic	0.000000
107.	c.223G>A	p.D75N	missense	1	VUS favour pathogenic	0.000091
108.	c.1678delG	p.Asp560ThrfsX19	frameshift	1	Pathogenic	0.000000
109.	c.333_334insT	p.E112X	nonsense	1	Pathogenic	0.000000
110.	c.2906-2A>G		essential splice site	1	Pathogenic	0.000000
111.	c.533delT	p.Val178GlyfsX7	frameshift	1	Pathogenic	0.000000
112.	c.2524_2525insT	p.Tyr842LeufsX42	frameshift	1	Pathogenic	0.000000
113.	c.1800delA		frameshift	1	Pathogenic	0.000000
114.	c.1273C>T	p.Q425X	nonsense	1	Pathogenic	0.000000
115.	c.1456T>G	p.W486G	missense	1	Likely Pathogenic	0.000000
116.	c.2518G>A	p.V840M	missense	1	VUS	0.000016
117.	c.1090+1G>T		essential splice site	1	Pathogenic	0.000000
118.	c.1672G>A	p.A558T	missense	1	VUS	0.000008
119.	c.3415G>A	p.V1139I	missense	1	VUS	0.000087
120.	c.2210C>T	p.T737M	missense	1	VUS	0.000050
121.	c.3476_3477delTT		frameshift	1	Pathogenic	0.000000
122.	c.3797G>A	p.C1266Y	missense	1	Likely Pathogenic	0.000000
123.	c.290C>T	p.A97V	missense	1	VUS favour pathogenic	0.000000
124.	c.373G>T	p.A125S	missense	1	VUS	0.000000
125.	c.2780_2781delCA		frameshift	1	Pathogenic	0.000000
126.	c.3083C>G	p.T1028S	missense	1	VUS	0.000000
127.	c.1351+1G>A		essential splice site	1	Pathogenic	0.000000
128.	c.2528_2536delAGATGCGCG	p.Glu843_Arg845del	inframe	1	Pathogenic	0.000000
129.	c.436A>C	p.T146P	missense	1	VUS	0.000000
130.	c.506-1G>T		essential splice site	1	Pathogenic	0.000000
131.	c.1999_2000delinsG	p.Leu667AspfsX15	frameshift	1	Pathogenic	0.000000
132.	c.1021G>A	p.G341S	missense	1	VUS favour pathogenic	0.000025
133.	c.326C>T	p.A109V	missense	1	VUS	0.000000
134.	c.2040_2041insT	p.Val681CysfsX12	frameshift	1	Pathogenic	0.000000
135.	c.1000G>T	p.E334X	nonsense	1	Pathogenic	0.000000
136.	c.2723A>G	p.Y908C	missense	1	VUS	0.000062
137.	c.3580G>A	p.A1194T	missense	1	VUS	0.000008
138.	c.3335G>A	p.W1112X	nonsense	1	Pathogenic	0.000000
139.	c.1188G>T	p.W396C	missense	1	VUS	0.000000
140.	c.1699_1700delGA	p.Glu567GlyfsX4	frameshift	1	Pathogenic	0.000000
141.	c.481C>A	p.P161T	missense	1	VUS favour pathogenic	0.000041
142.	c.2394_2395insT	p.Gly799TrpfsX34	frameshift	1	Pathogenic	0.000000
143.	c.931T>A	p.S311T	missense	1	VUS	0.000000
144.	c.3166_3167insG	p.Ala1056GlyfsX9	frameshift	1	Pathogenic	0.000000
145.	c.2747G>A	p.W916X	nonsense	1	Pathogenic	0.000000
146.	c.2965G>T	p.E989X	nonsense	1	Pathogenic	0.000000
147.	c.821+2T>C		essential splice site	1	Pathogenic	0.000000
148.	c.3476_3479dupTTAT	p.Pro1161TyrfsX9	frameshift	1	Pathogenic	0.000000
149.	c.932C>T	p.S311L	missense	1	VUS	0.000000
150.	c.1397T>A	p.M466K	missense	1	VUS	0.000008
151.	c.655-1G>A		essential splice site	1	Pathogenic	0.000000
152.	c.2993A>G	p.Q998R	missense	1	VUS favour pathogenic	0.000000
153.	c.2269G>A	p.V757M	missense	1	VUS	0.000066
154.	c.3811C>T	p.R1271X	nonsense	1	Pathogenic	0.000025
155.	c.3776delA		frameshift	1	Pathogenic	0.000000
156.	c.2828G>A	p.R943Q	missense	1	VUS	0.000025
157.	c.1213A>G	p.M405V	missense	1	Pathogenic	0.000000
158.	c.2671C>T	p.R891W	missense	1	Likely Pathogenic	0.000031
159.	c.1841A>G	p.Y614C	missense	1	VUS favour pathogenic	0.000000
160.	c.3825A>G	p.X1275TrpextX77	nonsense	1	Likely Pathogenic	0.000000
161.	c.451G>A	p.D151N	missense	1	VUS	0.000041
162.	c.2641G>A	p.V881I	missense	1	VUS	0.000018
163.	c.2939G>A	p.R980H	missense	1	VUS	0.000000
164.	c.1892delT		frameshift	1	Pathogenic	0.000000
165.	c.3815-1G>A		essential splice site	1	Pathogenic	0.000000
166.	c.2833_2834delCG		frameshift	1	Pathogenic	0.000000
167.	c.104G>A	p.R35Q	missense	1	VUS	0.000079
168.	c.3753T>G	p.Y1251X	nonsense	1	Pathogenic	0.000000
169.	c.2449C>T	p.R817W	missense	1	VUS	0.000000
170.	c.518C>A	p.T173N	missense	1	VUS	0.000000
171.	c.177_187del	p.Glu60AlafsX49	frameshift	1	Pathogenic	0.000000
172.	c.1950C>G	p.D650E	missense	1	VUS	0.000000
173.	c.1458-1G>A		essential splice site	1	Pathogenic	0.000000
174.	c.3331-1G>A		essential splice site	1	Pathogenic	0.000000
175.	c.551_552insT	p.Lys185GlufsX56	frameshift	1	Pathogenic	0.000000
176.	c.2541C>A	p.Y847X	nonsense	1	Pathogenic	0.000000
177.	c.1505G>T	p.R502L	missense	1	VUS favour pathogenic	0.000000
178.	c.2048G>A	p.W683X	nonsense	1	Pathogenic	0.000000
179.	c.3286G>T	p.E1096X	nonsense	1	Pathogenic	0.000000
180.	c.3288delG		frameshift	1	Pathogenic	0.000000
181.	c.2459G>A	p.R820Q	missense	1	Likely Pathogenic	0.000016
182.	c.713G>A	p.R238H	missense	1	VUS	0.000074
183.	c.2560A>G	p.M854V	missense	1	VUS	0.000000
184.	c.1156G>T	p.E386X	nonsense	1	Pathogenic	0.000000
185.	c.3098G>A	p.R1033Q	missense	1	VUS	0.000000
186.	c.1628delA		frameshift	1	Pathogenic	0.000000
187.	c.2610_2611insC	p.Ser871GlnfsX13	frameshift	1	Pathogenic	0.000000
188.	c.1090+1G>A		essential splice site	1	Pathogenic	0.000000
189.	c.3065G>A	p.R1022H	missense	1	VUS favour pathogenic	0.000000
190.	c.3746G>T	p.G1249V	missense	1	VUS	0.000000
191.	c.833delG	p.Gly278GlufsX22	frameshift	1	Pathogenic	0.000000
192.	c.2905+1G>C		essential splice site	1	Pathogenic	0.000000
193.	c.3068_3069insA	p.Asn1023LysfsX28	frameshift	1	Pathogenic	0.000000
194.	c.853G>A	p.D285N	missense	1	VUS	0.000000
195.	c.3694A>T	p.K1232X	nonsense	1	Pathogenic	0.000000
196.	c.2113_2114insA	p.Thr705AsnfsX3	frameshift	1	Pathogenic	0.000000
197.	c.1778C>T	p.S593F	missense	1	VUS favour pathogenic	0.000034
198.	c.3281A>T	p.N1094I	missense	1	VUS	0.000000
199.	c.1351+2T>C		essential splice site	1	Pathogenic	0.000000
200.	c.1418T>C	p.F473S	missense	1	VUS	0.000000
201.	c.2875_2876delAC	p.Thr959GlyfsX91	frameshift	1	Pathogenic	0.000000
202.	c.3690_3691delCA	p.Phe1230LeufsX11	frameshift	1	Pathogenic	0.000000
203.	c.2437A>T	p.K813X	nonsense	1	Pathogenic	0.000000
204.	c.3413G>C	p.R1138P	missense	1	VUS	0.000000
205.	c.3253G>T	p.E1085X	nonsense	1	Pathogenic	0.000000
206.	c.2312T>C	p.V771A	missense	1	VUS	0.000000
207.	c.993_994insT	p.E332X	nonsense	1	Pathogenic	0.000000
208.	c.1693A>T	p.K565X	nonsense	1	Pathogenic	0.000000
209.	c.2234A>G	p.D745G	missense	1	VUS	0.000000
210.	c.3065G>C	p.R1022P	missense	1	VUS favour pathogenic	0.000025
211.	c.844C>T	p.R282W	missense	1	VUS favour pathogenic	0.000000
212.	c.1591G>C	p.G531R	missense	1	VUS favour pathogenic	0.000017
213.	c.1540A>G	p.I514V	missense	1	VUS	0.000008
214.	c.1575T>G	p.Y525X	nonsense	1	Pathogenic	0.000000
215.	c.1038_1042dupCGGCA		frameshift	1	Pathogenic	0.000008
216.	c.3735delC		frameshift	1	Likely Pathogenic	0.000000
217.	c.2533C>T	p.R845C	missense	1	VUS favour pathogenic	0.000000
218.	c.3676C>T	p.R1226C	missense	1	VUS	0.000058
219.	c.1358C>T	p.P453L	missense	1	VUS	0.000008
220.	c.2490_2491insT	p.His831SerfsTer2	frameshift	1	Pathogenic	0.000024
221.	c.3049G>A	p.E1017K	missense	1	VUS favour benign	0.000085
222.	c.1224-2A>G		essential splice site	1	Pathogenic	0.000000
223.	c.2163delC	p.Glu722ArgfsX32	frameshift	1	Pathogenic	0.000000
224.	c.2308+1G>A		essential splice site	1	Pathogenic	0.000000
225.	c.2938C>T	p.R980C	missense	1	VUS	0.000062
226.	c.2170C>T	p.R724W	missense	1	VUS	0.000019
227.	c.3408C>A	p.Y1136X	nonsense	1	Pathogenic	0.000000
228.	c.459delC		frameshift	1	Pathogenic	0.000000
229.	c.2525A>G	p.Y842C	missense	1	VUS	0.000000
230.	c.2013_2016delinsGG	p.Pro672AspfsX20	frameshift	1	Pathogenic	0.000000
231.	c.3G>C	p.Met1?	missense	1	Likely Pathogenic	0.000000
232.	c.2557G>A	p.G853S	missense	1	VUS	0.000008
233.	c.3763G>A	p.A1255T	missense	1	VUS favour pathogenic	0.000075
234.	c.431_432delGT	p.Gly144AlafsX8	frameshift	1	Pathogenic	0.000000
235.	c.1294G>A	p.A432T	missense	1	VUS	0.000037
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.