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