LAMP2 variants in HCM cohorts


The table below lists the 10 rare (MAF<0.0001 in ExAC) protein-altering LAMP2 variants identified in a cohort of 2451 HCM patients. When this rare variant frequency of 0.00408 is compared with a background population rate of 0.00198, there is a statistically significant case excess of 0.00210 (p<0.0001), which suggests that approximately 5 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 (2451)LMM class ExAC frequency
1. c.928G>A p.V310Imissense 2Pathogenic0.000000
2. c.183+1G>A essential splice site 1Likely Pathogenic0.000000
3. c.824A>G p.N275Smissense 1VUS0.000000
4. c.864+1G>T essential splice site 1Pathogenic0.000000
5. c.56T>G p.L19Rmissense 1VUS favour pathogenic0.000000
6. c.517G>A p.V173Imissense 1VUS favour benign0.000034
7. c.371C>T p.T124Imissense 1VUS favour benign0.000000
8. c.929-1G>A essential splice site 1Likely Pathogenic0.000000
9. c.128_129dupAT p.Ala44MetfsX6frameshift 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.