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