TPM1 non-truncating variants in HCM cohorts


The table below lists the 44 rare (MAF<0.0001 in ExAC) non-truncating TPM1 variants identified in a cohort of 2912 HCM patients. When this rare variant frequency of 0.01511 is compared with a background population rate of 0.00084, there is a statistically significant case excess of 0.01427 (p<0.0001), which suggests that approximately 41 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 (2912)LMM class ExAC frequency
1. c.574G>A p.E192Kmissense 13Likely Pathogenic0.000000
2. c.523G>A p.D175Nmissense 4Pathogenic0.000000
3. c.644C>T p.S215Lmissense 3VUS favour pathogenic0.000008
4. c.829G>A p.A277Tmissense 2VUS favour benign0.000034
5. c.841A>G p.M281Vmissense 2VUS0.000026
6. c.82G>C p.D28Hmissense 2VUS favour pathogenic0.000000
7. c.64G>A p.A22Tmissense 2VUS favour pathogenic0.000000
8. c.457C>G p.H153Dmissense 1Pathogenic0.000000
9. c.343G>A p.E115Kmissense 1Likely Pathogenic0.000000
10. c.252C>G p.D84Emissense 1VUS0.000008
11. c.46G>C p.E16Qmissense 1Likely Pathogenic0.000000
12. c.676A>C p.K226Qmissense 1VUS favour pathogenic0.000000
13. c.790A>G p.K264Emissense 1Likely Pathogenic0.000000
14. c.82G>A p.D28Nmissense 1VUS0.000000
15. c.842T>C p.M281Tmissense 1VUS0.000000
16. c.58G>A p.D20Nmissense 1VUS0.000000
17. c.559G>C p.E187Qmissense 1Likely Pathogenic0.000000
18. c.655G>A p.D219Nmissense 1Likely Pathogenic0.000000
19. c.835A>C p.N279Hmissense 1VUS favour pathogenic0.000000
20. c.305C>A p.A102Dmissense 1VUS favour pathogenic0.000000
21. c.762T>G p.D254Emissense 1Likely Pathogenic0.000000
22. c.850A>G p.I284Vmissense 1VUS0.000000
23. c.548C>T p.A183Vmissense 1VUS0.000000

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.