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