ACTC1 variants in HCM cohorts


The table below lists the 22 rare (MAF<0.0001 in ExAC) protein-altering ACTC1 variants identified in a cohort of 4185 HCM patients (1535 patients from OMGL, 2650 patients from LMM). When this rare variant frequency of 0.00526 is compared with a background population rate of 0.00064, there is a statistically significant case excess of 0.00462 (p<0.0001), which suggests that approximately 19 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.301G>A p.E101Kmissense 5Pathogenic (1)Pathogenic (4)0.000008
2. c.793C>G p.Q265Emissense 2Likely Pathogenic (2)0.000000
3. c.850A>T p.I284Fmissense 2VUS (1)VUS (1)0.000000
4. c.76G>A p.D26Nmissense 2VUS (1)VUS favour pathogenic (1)0.000000
5. c.28C>A p.L10Mmissense 2VUS (2)0.000025
6. c.1069A>G p.M357Vmissense 1VUS (1)0.000000
7. c.83C>T p.A28Vmissense 1VUS (1)0.000000
8. c.124C>T p.H42Ymissense 1VUS (1)0.000000
9. c.229A>G p.I77Vmissense 1VUS (1)0.000024
10. c.797C>T p.P266Lmissense 1VUS (1)0.000000
11. c.268C>T p.H90Ymissense 1VUS (1)0.000008
12. c.1099G>A p.A367Tmissense 1VUS (1)0.000000
13. c.110T>C p.V37Amissense 1VUS (1)0.000000
14. c.752C>G p.T251Smissense 1VUS (1)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.