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