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

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.