1. Meeting summary and thoughts
Garry Cutting, MD
McKusick Nathans Institute of Genetic Medicine
Johns Hopkins
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2. Kudos
Scientific Programme Committee
Richard G. H. Cotton (Melbourne, Australia)
Raymond Dalgleish (Leicester, United Kingdom)
Johan T. den Dunnen (Leiden, Netherlands)
Marc Greenblatt (Burlington, VT, United States)
Aida Falcon de Vargas (Caracas, Venezuela)
Finlay Macrae (Melbourne, Australia)
Martina Witsch-Baumgartner (Innsbruck, Austria)
Organising Secretariat
Rania Horaitis, ICO
Heather Howard, ICO
Helen Robinson , ICO
Timothy Smith, ICO
Casimiro Vizzini, UNESCO

3. And finish on time
Don’t be boring

4. Annotating variation in the human genome
• The challenge
• Potential solutions
The Cambridge Wine Blogger
http://cambridgewineblogger.blogspot.com/2011/06/on-
breadth-vs-depth-in-tasting.html

5. Stylianos Antonarakis, Session VIII

9. Rapid increase in the number of genes
associated with mendelian phenotypes
Source: OMIM
Years
Numberofgenes

10. Number of variants reported per gene in the
Leiden Open Variation Database (LOVD)
Variants from LOVD databases version 2.0-24 or higher and with properly configured reference sequences were used to extract the number of unique
alleles reported per gene. If a gene was present in multiple databases (duplicate instances), the raw data was parsed such that the highest number of
variants per a given gene was reported. Data courtesy of Ivo F.A.C. Fokkema and Johan T. den Dunnen.
Figures courtesy of Melissa Lee Cutting GR AJHG 2014

11. • Increasing number of genes associated
with mendelian disease
• Increasing number of variants per gene
Perfect Storm of Variants

12. Interpretive gap: Difference between
rate of variant discovery and rate of
variant annotation
Variants identified
Interpretive
gap
Annotated
Cost of sequencing
Time
$$
Cutting GR AJHG 2014

13. Quantifying the interpretive gap
CFTR
137 for OMIM, 1301 for HGMD, 345 for LOVD
HBA1
HBB
Gene matched counts of variants per gene, sorted by length

14. Christopher Cassa, Session X

16. Stylianos Antonarakis, Session VIII

17. Thomy de Ravel, Session II

18. Nik Nor Liza Nik Hassan, Session II

19. Raj Ramesar, Session III

20. Dwomoa Adu, Session III

21. Enock Matovu, Session III

22. Stylianos Antonarakis, Session VIII

23. Ted Kalbfleisch, Session IV

24. Moris Swertz, Session IV

25. Stylianos Antonarakis, Session VIII

27. Peter Taschner, Session V

28. Raymond Dalgleish, Session V

29. Ada Hamosh, Session V

30. Stylianos Antonarakis, Session VIII

31. Hoan Nyugen, Session VIII

32. Tuuli Lappalainen, Session VIII

33. Variant Annotation Projects
• INSiGHT: International Society for Gastrointestinal
Hereditary Tumors
– Mismatch repair genes (Thompson et al Nat Genet 2014)
• CFTR2: Clinical and Functional Translation of CFTR
– CFTR (Sosnay et al Nat Genet 2013)
• ENIGMA :Evidence-based Network for the
Interpretation of Germline Mutant Alleles
– BRCA 1/2
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34. Maurizio Genuardi, Session IX

35. Finlay Macrae, Session IX

36. Christopher Cassa, Session X

38. Standards Development &
Recommended Systems
• HGVS variation nomenclature
• Mutalyzer
• LOVD
• VarioML
• Variation Ontology (VariO)
• W01:Disclaimer Statements on G/DSDBs
• WG02: Assigning Pathogenicity to a Genetic Variant
• WG03 Minimal content for gene variant databases (LSDBS)
• WG04 Minimum Content Requirements for HVP Country Nodes
• WG05: Variant Database Quality Assessment
• WG06: Disease &Phenotype Descriptions in Gene/Disease Specific
Databases
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39. Summary

40. Thank you for attending HVP5
sharing data · reducing disease
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