MYBPC3 non-truncating variants in HCM cohorts

The table below lists the 338 rare (MAF<0.0001 in ExAC) non-truncating MYBPC3 variants identified in a cohort of 3267 HCM patients. When this rare variant frequency of 0.10346 is compared with a background population rate of 0.01884, there is a statistically significant case excess of 0.08462 (p<0.0001), which suggests that approximately 277 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 (3267)▼	OMGL class	ExAC frequency
1.	c.1504C>T	p.R502W	missense	59	Pathogenic	0.000024
2.	c.772G>A	p.E258K	missense	47	Pathogenic	0.000039
3.	c.1624G>C	p.E542Q	missense	24	Pathogenic	0.000024
4.	c.655G>C	p.V219L	missense	18	Likely Pathogenic	0.000000
5.	c.2429G>A	p.R810H	missense	11	VUS	0.000033
6.	c.3613C>T	p.R1205W	missense	10	Likely Pathogenic	0.000016
7.	c.1483C>G	p.R495G	missense	10	Likely Pathogenic	0.000000
8.	c.3771C>A	p.N1257K	missense	9	Likely Pathogenic	0.000000
9.	c.3065G>C	p.R1022P	missense	5	Likely Pathogenic	0.000025
10.	c.2459G>A	p.R820Q	missense	5	VUS	0.000016
11.	c.2308G>A	p.D770N	missense	5	Likely Pathogenic	0.000008
12.	c.442G>A	p.G148R	missense	4	Likely Pathogenic	0.000042
13.	c.1484G>A	p.R495Q	missense	4	Likely Pathogenic	0.000008
14.	c.3798C>G	p.C1266W	missense	4	VUS	0.000000
15.	c.1123G>A	p.V375M	missense	3	VUS	0.000009
16.	c.710A>C	p.Y237S	missense	3	Likely Pathogenic	0.000000
17.	c.1720C>T	p.R574W	missense	3	VUS	0.000054
18.	c.2210C>T	p.T737M	missense	3	VUS	0.000050
19.	c.3277G>T	p.G1093C	missense	3	VUS	0.000020
20.	c.3763G>A	p.A1255T	missense	3	VUS	0.000075
21.	c.2573G>A	p.S858N	missense	2	Likely Pathogenic	0.000000
22.	c.1505G>A	p.R502Q	missense	2	Pathogenic	0.000000
23.	c.1886T>C	p.L629P	missense	2	VUS	0.000000
24.	c.1483C>T	p.R495W	missense	2	Likely Pathogenic	0.000000
25.	c.3752A>G	p.Y1251C	missense	2	VUS	0.000000
26.	c.3455_3466del	p.Ala1152_Lys1155del	inframe	2	Likely Pathogenic	0.000000
27.	c.2432A>G	p.K811R	missense	2	VUS	0.000000
28.	c.1828G>A	p.D610N	missense	2	VUS	0.000000
29.	c.2219G>C	p.G740A	missense	2	VUS	0.000000
30.	c.3005G>A	p.R1002Q	missense	2	VUS	0.000046
31.	c.557C>T	p.P186L	missense	2	VUS	0.000047
32.	c.3751T>C	p.Y1251H	missense	2	VUS	0.000000
33.	c.3470C>T	p.P1157L	missense	2	VUS	0.000093
34.	c.3582_3593delGGGCTACACTGC		inframe	2	Likely Pathogenic	0.000000
35.	c.2300A>G	p.K767R	missense	2	VUS	0.000016
36.	c.818G>A	p.R273H	missense	2	VUS	0.000042
37.	c.3373G>A	p.V1125M	missense	1	VUS	0.000022
38.	c.3614G>A	p.R1205Q	missense	1	VUS	0.000016
39.	c.1828G>C	p.D610H	missense	1	VUS	0.000058
40.	c.2249C>T	p.T750M	missense	1	Likely Pathogenic	0.000024
41.	c.1789C>T	p.R597W	missense	1	VUS	0.000038
42.	c.1456T>G	p.W486G	missense	1	VUS	0.000000
43.	c.1021G>A	p.G341S	missense	1	VUS	0.000025
44.	c.532G>A	p.V178M	missense	1	VUS	0.000020
45.	c.1213A>G	p.M405V	missense	1	VUS	0.000000
46.	c.3206C>A	p.P1069H	missense	1	Likely Pathogenic	0.000000
47.	c.3739G>A	p.D1247N	missense	1	VUS	0.000000
48.	c.2381C>A	p.P794Q	missense	1	VUS	0.000000
49.	c.1A>T	p.Met1?	missense	1	Likely Pathogenic	0.000000
50.	c.1174G>T	p.A392S	missense	1	VUS	0.000000
51.	c.3452C>T	p.A1151V	missense	1	VUS	0.000078
52.	c.3676C>T	p.R1226C	missense	1	VUS	0.000058
53.	c.3019T>C	p.W1007R	missense	1	VUS	0.000000
54.	c.2269G>A	p.V757M	missense	1	VUS	0.000066
55.	c.2873C>T	p.T958I	missense	1	VUS	0.000065
56.	c.1471G>A	p.V491M	missense	1	VUS	0.000058
57.	c.2197C>T	p.R733C	missense	1	Likely Pathogenic	0.000085
58.	c.1291G>A	p.D431N	missense	1	VUS	0.000028
59.	c.799C>G	p.L267V	missense	1	VUS	0.000080
60.	c.1037G>A	p.R346H	missense	1	VUS	0.000000
61.	c.844C>T	p.R282W	missense	1	Likely Pathogenic	0.000000
62.	c.188G>A	p.R63Q	missense	1	VUS	0.000039
63.	c.3334_3351del	p.Trp1112_Glu1117del	inframe	1	Likely Pathogenic	0.000000
64.	c.256_258del	p.Ser86del	inframe	1	VUS	0.000000
65.	c.1455A>T	p.K485N	missense	1	VUS	0.000000
66.	c.2834G>A	p.R945Q	missense	1	VUS	0.000000
67.	c.3572C>T	p.S1191L	missense	1	VUS	0.000016
68.	c.701C>A	p.T234N	missense	1	Likely Pathogenic	0.000000
69.	c.3713T>C	p.L1238P	missense	1	Likely Pathogenic	0.000000
70.	c.3316G>A	p.D1106N	missense	1	VUS	0.000061
71.	c.2504G>T	p.R835L	missense	1	Likely Pathogenic	0.000074
72.	c.1112C>T	p.P371L	missense	1	VUS	0.000028
73.	c.1433C>T	p.S478L	missense	1	Likely Pathogenic	0.000017
74.	c.1153G>A	p.V385M	missense	1	VUS	0.000010
75.	c.49C>T	p.R17W	missense	1	VUS	0.000023
76.	c.994G>A	p.E332K	missense	1	VUS	0.000009
77.	c.1756C>G	p.P586A	missense	1	Likely Pathogenic	0.000000
78.	c.146_148delTCA	p.Ile49del	inframe	1	VUS	0.000039
79.	c.2968C>G	p.P990A	missense	1	Likely Pathogenic	0.000000
80.	c.3728C>G	p.P1243R	missense	1	VUS	0.000000
81.	c.1097A>C	p.Q366P	missense	1	VUS	0.000000
82.	c.3656T>C	p.L1219P	missense	1	VUS	0.000000
83.	c.2265C>A	p.N755K	missense	1	Pathogenic	0.000000
84.	c.3064C>T	p.R1022C	missense	1	VUS	0.000008
85.	c.2449C>T	p.R817W	missense	1	VUS	0.000000
86.	c.1841A>G	p.Y614C	missense	1	VUS	0.000000
87.	c.1790G>A	p.R597Q	missense	1	VUS	0.000000
88.	c.2030C>T	p.P677L	missense	1	VUS	0.000000
89.	c.1591G>A	p.G531R	missense	1	Likely Pathogenic	0.000017
90.	c.1021G>C	p.G341R	missense	1	VUS	0.000000
91.	c.631G>A	p.D211N	missense	1	VUS	0.000009
92.	c.187C>T	p.R63W	missense	1	VUS	0.000077
93.	c.3256T>C	p.W1086R	missense	1	VUS	0.000000
94.	c.2708G>A	p.G903D	missense	1	Likely Pathogenic	0.000000
95.	c.241G>T	p.V81F	missense	1	VUS	0.000000
96.	c.3364A>T	p.T1122S	missense	1	Likely Pathogenic	0.000000
97.	c.1231A>G	p.I411V	missense	1	VUS	0.000000
98.	c.2503C>T	p.R835C	missense	1	VUS	0.000024
99.	c.2909G>A	p.R970Q	missense	1	Likely Pathogenic	0.000032
100.	c.2198G>A	p.R733H	missense	1	VUS	0.000034
101.	c.1685C>T	p.A562V	missense	1	VUS	0.000008
102.	c.1072G>A	p.D358N	missense	1	VUS	0.000008
103.	c.373G>T	p.A125S	missense	1	VUS	0.000000
104.	c.1731G>C	p.W577C	missense	1	VUS	0.000000
105.	c.148A>G	p.S50G	missense	1	VUS	0.000038
106.	c.2953A>G	p.K985E	missense	1	Pathogenic	0.000000
107.	c.365C>A	p.A122D	missense	1	VUS	0.000000
108.	c.3614G>C	p.R1205P	missense	1	Likely Pathogenic	0.000000
109.	c.1080G>C	p.K360N	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.