MYL3 variants in HCM cohorts

The table below lists the 37 rare (MAF<0.0001 in ExAC) protein-altering MYL3 variants identified in a cohort of 4185 HCM patients (1535 patients from OMGL, 2650 patients from LMM). When this rare variant frequency of 0.00884 is compared with a background population rate of 0.00182, there is a statistically significant case excess of 0.00702 (p<0.0001), which suggests that approximately 29 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 (4185)OMGL classLMM class ExAC frequency
1. c.281G>A p.R94Hmissense 4Likely Pathogenic (4)0.000000
2. c.461G>A p.R154Hmissense 3VUS (1)VUS favour pathogenic (2)0.000024
3. c.460C>T p.R154Cmissense 3VUS (1)VUS favour pathogenic (2)0.000016
4. c.427G>A p.E143Kmissense 3VUS (3)0.000000
5. c.463C>G p.H155Dmissense 2Pathogenic (2)0.000000
6. c.517A>G p.M173Vmissense 2VUS favour pathogenic (2)0.000000
7. c.170C>G p.A57Gmissense 2Likely Pathogenic (2)0.000090
8. c.383G>A p.G128Dmissense 2VUS (2)0.000000
9. c.466G>A p.V156Mmissense 2VUS (2)0.000016
10. c.454G>A p.E152Kmissense 1VUS (1)0.000000
11. c.466G>T p.V156Lmissense 1VUS (1)0.000000
12. c.128A>C p.K43Tmissense 1VUS (1)0.000000
13. c.539A>G p.N180Smissense 1VUS (1)0.000000
14. c.187C>T p.R63Cmissense 1VUS (1)0.000008
15. c.521C>T p.A174Vmissense 1VUS (1)0.000008
16. c.445A>G p.M149Vmissense 1Pathogenic (1)0.000000
17. c.64G>T p.A22Smissense 1VUS (1)0.000000
18. c.520G>C p.A174Pmissense 1VUS (1)0.000000
19. c.11A>G p.K4Rmissense 1VUS (1)0.000000
20. c.466G>C p.V156Lmissense 1VUS (1)0.000000
21. c.188G>A p.R63Hmissense 1VUS (1)0.000024
22. c.446T>C p.M149Tmissense 1VUS (1)0.000008
23. c.338C>T p.T113Imissense 1VUS (1)0.000000


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.