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