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