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