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