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