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