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

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.