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