GLA variants in HCM cohorts


The table below lists the 27 rare (MAF<0.0001 in ExAC) protein-altering GLA variants identified in a cohort of 3700 HCM patients (1535 patients from OMGL, 2165 patients from LMM). When this rare variant frequency of 0.00730 is compared with a background population rate of 0.00100, there is a statistically significant case excess of 0.00630 (p<0.0001), which suggests that approximately 23 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 (3700)OMGL classLMM class ExAC frequency
1. c.644A>G p.N215Smissense 13Pathogenic (10)Pathogenic (3)0.000000
2. c.961C>G p.Q321Emissense 1Likely Pathogenic (1)0.000000
3. c.729G>C p.L243Fmissense 1VUS favour pathogenic (1)0.000000
4. c.1117G>A p.G373Smissense 1Likely Pathogenic (1)0.000000
5. c.525C>G p.D175Emissense 1VUS (1)0.000000
6. c.829T>G p.W277Gmissense 1VUS (1)0.000000
7. c.700_702delGAT inframe 1Likely Pathogenic (1)0.000000
8. c.70T>A p.W24Rmissense 1VUS (1)0.000000
9. c.782G>T p.G261Vmissense 1Likely Pathogenic (1)0.000000
10. c.1168G>A p.V390Mmissense 1VUS (1)0.000000
11. c.613C>A p.P205Tmissense 1Pathogenic (1)0.000000
12. c.691G>A p.D231Nmissense 1Pathogenic (1)0.000000
13. c.485G>T p.W162Lmissense 1VUS (1)0.000000
14. c.1066C>T p.R356Wmissense 1Pathogenic (1)0.000000
15. c.776C>G p.P259Rmissense 1Likely Pathogenic (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.