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.2518G>A	p.V840M	missense	1	VUS	0.000016
2.	c.1672G>A	p.A558T	missense	1	VUS	0.000008
3.	c.2312T>C	p.V771A	missense	1	VUS	0.000000
4.	c.3083C>G	p.T1028S	missense	1	VUS	0.000000
5.	c.3415G>A	p.V1139I	missense	1	VUS	0.000087
6.	c.2210C>T	p.T737M	missense	1	VUS	0.000050
7.	c.373G>T	p.A125S	missense	1	VUS	0.000000
8.	c.1586C>G	p.T529S	missense	1	VUS favour pathogenic	0.000000
9.	c.2436G>T	p.K812N	missense	1	VUS	0.000000
10.	c.2723A>G	p.Y908C	missense	1	VUS	0.000062
11.	c.1934C>T	p.P645L	missense	2	VUS	0.000000
12.	c.2459G>A	p.R820Q	missense	1	Likely Pathogenic	0.000016
13.	c.355G>A	p.E119K	missense	3	VUS	0.000000
14.	c.2374T>C	p.W792R	missense	5	Likely Pathogenic	0.000000
15.	c.442G>A	p.G148R	missense	7	VUS favour pathogenic	0.000042
16.	c.772G>A	p.E258K	missense	21	Pathogenic	0.000039
17.	c.1591G>C	p.G531R	missense	1	VUS favour pathogenic	0.000017
18.	c.3064C>T	p.R1022C	missense	4	VUS favour pathogenic	0.000008
19.	c.3797G>A	p.C1266Y	missense	1	Likely Pathogenic	0.000000
20.	c.2882C>T	p.P961L	missense	2	VUS	0.000048
21.	c.1483C>T	p.R495W	missense	2	VUS favour pathogenic	0.000000
22.	c.2269G>A	p.V757M	missense	1	VUS	0.000066
23.	c.1960C>T	p.R654C	missense	1	VUS favour benign	0.000008
24.	c.932C>T	p.S311L	missense	1	VUS	0.000000
25.	c.1397T>A	p.M466K	missense	1	VUS	0.000008
26.	c.2197C>T	p.R733C	missense	1	VUS	0.000085
27.	c.2828G>A	p.R943Q	missense	1	VUS	0.000025
28.	c.104G>A	p.R35Q	missense	1	VUS	0.000079
29.	c.3548T>G	p.F1183C	missense	1	Likely Pathogenic	0.000000
30.	c.451G>A	p.D151N	missense	1	VUS	0.000041
31.	c.1505G>T	p.R502L	missense	1	VUS favour pathogenic	0.000000
32.	c.326C>T	p.A109V	missense	1	VUS	0.000000
33.	c.1188G>T	p.W396C	missense	1	VUS	0.000000
34.	c.436A>C	p.T146P	missense	1	VUS	0.000000
35.	c.290C>T	p.A97V	missense	1	VUS favour pathogenic	0.000000
36.	c.1483C>G	p.R495G	missense	4	Likely Pathogenic	0.000000
37.	c.931T>A	p.S311T	missense	1	VUS	0.000000
38.	c.2429G>A	p.R810H	missense	8	VUS favour pathogenic	0.000033
39.	c.1343T>C	p.F448S	missense	1	Likely Pathogenic	0.000000
40.	c.2573G>A	p.S858N	missense	4	VUS favour pathogenic	0.000000
41.	c.2450G>A	p.R817Q	missense	3	VUS favour pathogenic	0.000016
42.	c.1504C>T	p.R502W	missense	45	Pathogenic	0.000024
43.	c.814C>T	p.R272C	missense	2	VUS	0.000083
44.	c.1778C>T	p.S593F	missense	1	VUS favour pathogenic	0.000034
45.	c.2560A>G	p.M854V	missense	1	VUS	0.000000
46.	c.713G>A	p.R238H	missense	1	VUS	0.000074
47.	c.3746G>T	p.G1249V	missense	1	VUS	0.000000
48.	c.3605G>A	p.C1202Y	missense	1	Likely Pathogenic	0.000000
49.	c.3098G>A	p.R1033Q	missense	1	VUS	0.000000
50.	c.2320G>A	p.A774T	missense	2	VUS	0.000000
51.	c.2939G>A	p.R980H	missense	1	VUS	0.000000
52.	c.1841A>G	p.Y614C	missense	1	VUS favour pathogenic	0.000000
53.	c.2449C>T	p.R817W	missense	1	VUS	0.000000
54.	c.1950C>G	p.D650E	missense	1	VUS	0.000000
55.	c.3373G>A	p.V1125M	missense	1	VUS favour pathogenic	0.000022
56.	c.518C>A	p.T173N	missense	1	VUS	0.000000
57.	c.655G>C	p.V219L	missense	8	Likely Pathogenic	0.000000
58.	c.1456T>G	p.W486G	missense	1	Likely Pathogenic	0.000000
59.	c.1484G>A	p.R495Q	missense	10	VUS favour pathogenic	0.000008
60.	c.3580G>A	p.A1194T	missense	1	VUS	0.000008
61.	c.532G>A	p.V178M	missense	2	VUS favour pathogenic	0.000020
62.	c.3763G>A	p.A1255T	missense	1	VUS favour pathogenic	0.000075
63.	c.2234A>G	p.D745G	missense	1	VUS	0.000000
64.	c.1213A>G	p.M405V	missense	1	Pathogenic	0.000000
65.	c.1540A>G	p.I514V	missense	1	VUS	0.000008
66.	c.2873C>T	p.T958I	missense	3	VUS favour benign	0.000065
67.	c.1828G>C	p.D610H	missense	2	VUS favour benign	0.000058
68.	c.2938C>T	p.R980C	missense	1	VUS	0.000062
69.	c.2170C>T	p.R724W	missense	1	VUS	0.000019
70.	c.3676C>T	p.R1226C	missense	1	VUS	0.000058
71.	c.1358C>T	p.P453L	missense	1	VUS	0.000008
72.	c.3049G>A	p.E1017K	missense	1	VUS favour benign	0.000085
73.	c.1535T>A	p.L512Q	missense	1	VUS favour pathogenic	0.000000
74.	c.1294G>A	p.A432T	missense	1	VUS	0.000037
75.	c.2557G>A	p.G853S	missense	1	VUS	0.000008
76.	c.2308G>A	p.D770N	missense	6	Likely Pathogenic	0.000008
77.	c.853G>A	p.D285N	missense	1	VUS	0.000000
78.	c.3065G>A	p.R1022H	missense	1	VUS favour pathogenic	0.000000
79.	c.3281A>T	p.N1094I	missense	1	VUS	0.000000
80.	c.1418T>C	p.F473S	missense	1	VUS	0.000000
81.	c.1505G>A	p.R502Q	missense	6	Pathogenic	0.000000
82.	c.1591G>A	p.G531R	missense	3	VUS favour pathogenic	0.000017
83.	c.3065G>C	p.R1022P	missense	1	VUS favour pathogenic	0.000025
84.	c.2671C>T	p.R891W	missense	1	Likely Pathogenic	0.000031
85.	c.2641G>A	p.V881I	missense	1	VUS	0.000018
86.	c.636C>G	p.S212R	missense	2	VUS favour pathogenic	0.000000
87.	c.3742G>A	p.G1248R	missense	1	VUS	0.000033
88.	c.103C>T	p.R35W	missense	1	VUS	0.000056
89.	c.2654C>T	p.T885M	missense	1	VUS	0.000022
90.	c.1828G>A	p.D610N	missense	3	VUS	0.000000
91.	c.3791G>A	p.C1264Y	missense	1	VUS	0.000008
92.	c.3G>C	p.Met1?	missense	1	Likely Pathogenic	0.000000
93.	c.3277G>T	p.G1093C	missense	1	VUS	0.000020
94.	c.2525A>G	p.Y842C	missense	1	VUS	0.000000
95.	c.1037G>A	p.R346H	missense	2	VUS	0.000000
96.	c.3413G>C	p.R1138P	missense	1	VUS	0.000000
97.	c.2533C>T	p.R845C	missense	1	VUS favour pathogenic	0.000000
98.	c.566T>A	p.V189D	missense	1	VUS	0.000000
99.	c.1624G>C	p.E542Q	missense	17	Likely Pathogenic	0.000024
100.	c.710A>C	p.Y237S	missense	3	Likely Pathogenic	0.000000
101.	c.223G>A	p.D75N	missense	1	VUS favour pathogenic	0.000091
102.	c.2993A>G	p.Q998R	missense	1	VUS favour pathogenic	0.000000
103.	c.1790G>A	p.R597Q	missense	2	VUS favour pathogenic	0.000000
104.	c.844C>T	p.R282W	missense	1	VUS favour pathogenic	0.000000
105.	c.1021G>A	p.G341S	missense	1	VUS favour pathogenic	0.000025
106.	c.481C>A	p.P161T	missense	1	VUS favour pathogenic	0.000041
107.	c.1766G>A	p.R589H	missense	2	VUS	0.000000
108.	c.2528_2536delAGATGCGCG	p.Glu843_Arg845del	inframe	1	Pathogenic	0.000000
109.	c.1513_1515delAAG		inframe	2	VUS favour pathogenic	0.000000
110.	c.3767_3769delCCA	p.Thr1256del	inframe	3	Likely Pathogenic	0.000000
111.	c.3742_3759dup	p.Gly1248_Cys1253dup	inframe	4	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.