TPM1 variants in HCM cohorts


The table below lists the 22 rare (MAF<0.0001 in ExAC) protein-altering TPM1 variants identified in a cohort of 1535 HCM patients. When this rare variant frequency of 0.01433 is compared with a background population rate of 0.00086, there is a statistically significant case excess of 0.01347 (p<0.0001), which suggests that approximately 21 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 (1535)OMGL class ExAC frequency
1. c.523G>A p.D175Nmissense 4Pathogenic0.000000
2. c.746T>G p.L249Wmissense 2Likely Pathogenic0.000000
3. c.548C>T p.A183Vmissense 2VUS0.000000
4. c.797A>G p.K266Rmissense 2VUS0.000042
5. c.481A>G p.K161Emissense 1VUS0.000000
6. c.774C>G p.D258Emissense 1VUS0.000000
7. c.850A>G p.I284Vmissense 1VUS0.000000
8. c.715G>A p.A239Tmissense 1VUS0.000000
9. c.677A>G p.K226Rmissense 1VUS0.000000
10. c.302G>C p.R101Pmissense 1VUS0.000000
11. c.82G>C p.D28Hmissense 1VUS0.000000
12. c.475G>A p.D159Nmissense 1VUS0.000000
13. c.761A>G p.D254Gmissense 1VUS0.000000
14. c.644C>T p.S215Lmissense 1VUS0.000008
15. c.699G>C p.K233Nmissense 1VUS0.000000
16. c.461T>C p.I154Tmissense 1Pathogenic0.000000

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.