MYBPC3 non-truncating variants in HCM cohorts

The table below lists the 272 rare (MAF<0.0001 in ExAC) non-truncating MYBPC3 variants identified in a cohort of 2912 HCM patients. When this rare variant frequency of 0.09341 is compared with a background population rate of 0.01884, there is a statistically significant case excess of 0.07457 (p<0.0001), which suggests that approximately 218 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.1591G>C	p.G531R	missense	1	VUS favour pathogenic	0.000017
2.	c.2374T>C	p.W792R	missense	5	Likely Pathogenic	0.000000
3.	c.442G>A	p.G148R	missense	7	VUS favour pathogenic	0.000042
4.	c.772G>A	p.E258K	missense	21	Pathogenic	0.000039
5.	c.2882C>T	p.P961L	missense	2	VUS	0.000048
6.	c.1483C>T	p.R495W	missense	2	VUS favour pathogenic	0.000000
7.	c.3064C>T	p.R1022C	missense	4	VUS favour pathogenic	0.000008
8.	c.3797G>A	p.C1266Y	missense	1	Likely Pathogenic	0.000000
9.	c.932C>T	p.S311L	missense	1	VUS	0.000000
10.	c.1397T>A	p.M466K	missense	1	VUS	0.000008
11.	c.2197C>T	p.R733C	missense	1	VUS	0.000085
12.	c.2269G>A	p.V757M	missense	1	VUS	0.000066
13.	c.1960C>T	p.R654C	missense	1	VUS favour benign	0.000008
14.	c.2828G>A	p.R943Q	missense	1	VUS	0.000025
15.	c.1505G>T	p.R502L	missense	1	VUS favour pathogenic	0.000000
16.	c.104G>A	p.R35Q	missense	1	VUS	0.000079
17.	c.3548T>G	p.F1183C	missense	1	Likely Pathogenic	0.000000
18.	c.451G>A	p.D151N	missense	1	VUS	0.000041
19.	c.1188G>T	p.W396C	missense	1	VUS	0.000000
20.	c.436A>C	p.T146P	missense	1	VUS	0.000000
21.	c.290C>T	p.A97V	missense	1	VUS favour pathogenic	0.000000
22.	c.326C>T	p.A109V	missense	1	VUS	0.000000
23.	c.2429G>A	p.R810H	missense	8	VUS favour pathogenic	0.000033
24.	c.1483C>G	p.R495G	missense	4	Likely Pathogenic	0.000000
25.	c.931T>A	p.S311T	missense	1	VUS	0.000000
26.	c.2450G>A	p.R817Q	missense	3	VUS favour pathogenic	0.000016
27.	c.1504C>T	p.R502W	missense	45	Pathogenic	0.000024
28.	c.1343T>C	p.F448S	missense	1	Likely Pathogenic	0.000000
29.	c.2573G>A	p.S858N	missense	4	VUS favour pathogenic	0.000000
30.	c.814C>T	p.R272C	missense	2	VUS	0.000083
31.	c.1778C>T	p.S593F	missense	1	VUS favour pathogenic	0.000034
32.	c.713G>A	p.R238H	missense	1	VUS	0.000074
33.	c.2560A>G	p.M854V	missense	1	VUS	0.000000
34.	c.2320G>A	p.A774T	missense	2	VUS	0.000000
35.	c.3746G>T	p.G1249V	missense	1	VUS	0.000000
36.	c.3605G>A	p.C1202Y	missense	1	Likely Pathogenic	0.000000
37.	c.3098G>A	p.R1033Q	missense	1	VUS	0.000000
38.	c.2449C>T	p.R817W	missense	1	VUS	0.000000
39.	c.2939G>A	p.R980H	missense	1	VUS	0.000000
40.	c.1841A>G	p.Y614C	missense	1	VUS favour pathogenic	0.000000
41.	c.518C>A	p.T173N	missense	1	VUS	0.000000
42.	c.1950C>G	p.D650E	missense	1	VUS	0.000000
43.	c.3373G>A	p.V1125M	missense	1	VUS favour pathogenic	0.000022
44.	c.1456T>G	p.W486G	missense	1	Likely Pathogenic	0.000000
45.	c.1484G>A	p.R495Q	missense	10	VUS favour pathogenic	0.000008
46.	c.655G>C	p.V219L	missense	8	Likely Pathogenic	0.000000
47.	c.2234A>G	p.D745G	missense	1	VUS	0.000000
48.	c.1213A>G	p.M405V	missense	1	Pathogenic	0.000000
49.	c.3580G>A	p.A1194T	missense	1	VUS	0.000008
50.	c.532G>A	p.V178M	missense	2	VUS favour pathogenic	0.000020
51.	c.3763G>A	p.A1255T	missense	1	VUS favour pathogenic	0.000075
52.	c.1828G>C	p.D610H	missense	2	VUS favour benign	0.000058
53.	c.1540A>G	p.I514V	missense	1	VUS	0.000008
54.	c.2873C>T	p.T958I	missense	3	VUS favour benign	0.000065
55.	c.1358C>T	p.P453L	missense	1	VUS	0.000008
56.	c.3049G>A	p.E1017K	missense	1	VUS favour benign	0.000085
57.	c.2938C>T	p.R980C	missense	1	VUS	0.000062
58.	c.2170C>T	p.R724W	missense	1	VUS	0.000019
59.	c.3676C>T	p.R1226C	missense	1	VUS	0.000058
60.	c.2557G>A	p.G853S	missense	1	VUS	0.000008
61.	c.1535T>A	p.L512Q	missense	1	VUS favour pathogenic	0.000000
62.	c.1294G>A	p.A432T	missense	1	VUS	0.000037
63.	c.1418T>C	p.F473S	missense	1	VUS	0.000000
64.	c.2308G>A	p.D770N	missense	6	Likely Pathogenic	0.000008
65.	c.853G>A	p.D285N	missense	1	VUS	0.000000
66.	c.3065G>A	p.R1022H	missense	1	VUS favour pathogenic	0.000000
67.	c.3281A>T	p.N1094I	missense	1	VUS	0.000000
68.	c.1505G>A	p.R502Q	missense	6	Pathogenic	0.000000
69.	c.1591G>A	p.G531R	missense	3	VUS favour pathogenic	0.000017
70.	c.2641G>A	p.V881I	missense	1	VUS	0.000018
71.	c.636C>G	p.S212R	missense	2	VUS favour pathogenic	0.000000
72.	c.3065G>C	p.R1022P	missense	1	VUS favour pathogenic	0.000025
73.	c.2671C>T	p.R891W	missense	1	Likely Pathogenic	0.000031
74.	c.3742G>A	p.G1248R	missense	1	VUS	0.000033
75.	c.1828G>A	p.D610N	missense	3	VUS	0.000000
76.	c.103C>T	p.R35W	missense	1	VUS	0.000056
77.	c.2654C>T	p.T885M	missense	1	VUS	0.000022
78.	c.3277G>T	p.G1093C	missense	1	VUS	0.000020
79.	c.3791G>A	p.C1264Y	missense	1	VUS	0.000008
80.	c.3G>C	p.Met1?	missense	1	Likely Pathogenic	0.000000
81.	c.3413G>C	p.R1138P	missense	1	VUS	0.000000
82.	c.2533C>T	p.R845C	missense	1	VUS favour pathogenic	0.000000
83.	c.2525A>G	p.Y842C	missense	1	VUS	0.000000
84.	c.1037G>A	p.R346H	missense	2	VUS	0.000000
85.	c.1624G>C	p.E542Q	missense	17	Likely Pathogenic	0.000024
86.	c.566T>A	p.V189D	missense	1	VUS	0.000000
87.	c.1790G>A	p.R597Q	missense	2	VUS favour pathogenic	0.000000
88.	c.844C>T	p.R282W	missense	1	VUS favour pathogenic	0.000000
89.	c.710A>C	p.Y237S	missense	3	Likely Pathogenic	0.000000
90.	c.223G>A	p.D75N	missense	1	VUS favour pathogenic	0.000091
91.	c.2993A>G	p.Q998R	missense	1	VUS favour pathogenic	0.000000
92.	c.481C>A	p.P161T	missense	1	VUS favour pathogenic	0.000041
93.	c.1766G>A	p.R589H	missense	2	VUS	0.000000
94.	c.1021G>A	p.G341S	missense	1	VUS favour pathogenic	0.000025
95.	c.2518G>A	p.V840M	missense	1	VUS	0.000016
96.	c.1672G>A	p.A558T	missense	1	VUS	0.000008
97.	c.2312T>C	p.V771A	missense	1	VUS	0.000000
98.	c.373G>T	p.A125S	missense	1	VUS	0.000000
99.	c.3083C>G	p.T1028S	missense	1	VUS	0.000000
100.	c.3415G>A	p.V1139I	missense	1	VUS	0.000087
101.	c.2210C>T	p.T737M	missense	1	VUS	0.000050
102.	c.2723A>G	p.Y908C	missense	1	VUS	0.000062
103.	c.1586C>G	p.T529S	missense	1	VUS favour pathogenic	0.000000
104.	c.2436G>T	p.K812N	missense	1	VUS	0.000000
105.	c.355G>A	p.E119K	missense	3	VUS	0.000000
106.	c.1934C>T	p.P645L	missense	2	VUS	0.000000
107.	c.2459G>A	p.R820Q	missense	1	Likely Pathogenic	0.000016
108.	c.1513_1515delAAG		inframe	2	VUS favour pathogenic	0.000000
109.	c.3767_3769delCCA	p.Thr1256del	inframe	3	Likely Pathogenic	0.000000
110.	c.3742_3759dup	p.Gly1248_Cys1253dup	inframe	4	Likely Pathogenic	0.000000
111.	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.