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