The Human Variome Project (HVP) 2009 Forum “Towards Establishing Standards”

Article (PDF Available)inHuman Mutation 31(3):366-7 · March 2010with22 Reads
DOI: 10.1002/humu.21175 · Source: PubMed
The May 2009 Human Variome Project (HVP) Forum "Towards Establishing Standards" was a round table discussion attended by delegates from groups representing international efforts aimed at standardizing several aspects of the HVP: mutation nomenclature, description and annotation, clinical ontology, means to better characterize unclassified variants (UVs), and methods to capture mutations from diagnostic laboratories for broader distribution to the medical genetics research community. Methods for researchers to receive credit for their effort at mutation detection were also discussed.

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Human Mutation
The Human Variome Project (HVP) 2009 Forum ‘‘Towards
Establishing Standards’’
Heather J. Howard,
Ourania Horaitis,
Richard G.H. Cotton,
Mauno Vihinen,
Raymond Dalgleish,
Peter Robinson,
Anthony J. Brookes,
Myles Axton,
Robert Hoffmann,
and Sylvie Tuffery-Giraud
Genomic Disorders Research Centre, Carlton South, Victoria, Australia;
The Department of Medicine, University of Melbourne VIC, Australia;
Institute of Medical Technology, University of Tampere, Finland and Tampere University Hospital, Tampere, Finland;
Department of Genetics,
University of Leicester, Leicester, United Kingdom;
Institut fu¨r Medizinische Genetik, Universita
¨tsklinikum Charite, Humboldt-Universita
¨t, Berlin,
Nature Genetics, New York, New York;
Computer Science and Artificial Intelligence Laboratory, Cambridge, Massachusetts;
Laboratoire de Ge
´tique Moleculaire, Institut Universitaire de Recherche Clinique and CHU, Montpellier, France
Received 13 October 2009; accepted revised manuscript 16 November 2009.
Published online 5 January 2010 in Wiley InterScience ( DOI 10.1002/humu.21175
ABSTRACT: The May 2009 Human Variome Project
(HVP) Forum ‘‘Towards Establishing Standards’’ was a
round table discussion attended by delegates from groups
representing international efforts aimed at standardizing
several aspects of the HVP: mutation nomenclature,
description and annotation, clinical ontology, means to
better characterize unclassified variants (UVs), and
methods to capture mutations from diagnostic labora-
tories for broader distribution to the medical genetics
research community. Methods for researchers to receive
credit for their effort at mutation detection were also
Hum Mutat 31:366–367, 2010. &2010 Wiley-Liss, Inc.
KEY WORDS: mutation; database; HVP; SNP; genetic
The Human Variome Project (HVP) Forum ‘‘Towards Estab-
lishing Standards’’ was held on 22 May, 2009 at the Hilton Vienna
Danube Hotel, on the banks of the river Danube in the imperial
city of Vienna, Austria. The round table discussion was attended
by 30 delegates from groups representing efforts to standardize
mutation nomenclature, clinical ontology, systems and ways to
capture mutations from diagnostic laboratories, methods to
receive credit for effort and communication of work.
The meeting started with a welcome by Richard Cotton, who
outlined the present status of the HVP. This included the
initiation of a HVP Node consortium, with country-specific
nodes. A pilot node is beginning in Australia and several other
countries including South Korea. The International Society for
Gastrointestinal Hereditary Tumours (InSiGHT; www.insight- Pilot is progressing well.
Johan den Dunnen spoke on describing complex sequence
variants by extending HGVS sequence variation nomenclature
[Antonarakis and Nomenclature Working Group, 1998] and advised
the attendees that he and colleagues are in the process of writing an
update paper on the subject. The meeting concluded that there was a
need for universal nomenclature across all genetic disciplines and
Mauno Vihinen outlined the VariO system, an ontology with
which the consequences of genetic variations can be described. The
system could be integrated with other systems such as the HGVS
variation nomenclature. VariO will also provide additional
information on data available in databases, currently about 500
terms are available and the system will be open for discussion soon.
The Locus Reference Genomic (LRG) DNA sequence format for
LSDBs was presented by Raymond Dalgleish, who addressed the
need for an improved reference sequence format better suited to
describing variants. The key features of LRGs are that the DNA
sequence is locked, avoiding the confusion with sequence versions
and that the sequence of all transcripts necessary to describe a
variant are also included, along with their conceptual translated-
protein sequences. The issues around legacy nomenclature were
discussed and it was concluded that legacy descriptions of variants
would need to be reported, at least for the present, in parallel with
systematic descriptions. A paper describing LRGs was being
prepared for publication and further information about LRGs can
be found at
Issues surrounding phenotype ontologies were addressed by
Peter Robinson, whose group has created a tool, the Human
Phenotype Ontology (HPO), that will allow large-scale computa-
tional analysis of the human phenome. The HPO currently
contains over 9,500 terms, each of which describes an individual
phenotypic abnormality. The exciting development with this
system is the ability to search across the many terms used to
describe the same condition. The HPO is freely available under an
open-source license at
Anthony Brookes outlined progress in the GEN2PHEN project
regarding the development of standards. He described the PaGE-
OM ( [Brookes et al., 2009]) object model for
genotype-phenotype data which offers a solid basis for the design
of data depositories, data exchange formats, and tools for data
curation. He also outlined ideas for the use of ‘‘digital IDs’’ by
which researchers can be unambiguously identified as they
contribute to, and access data from, internet resources.
The problems surrounding clinical documentation was graphi-
cally described by Rolf Sijmons. Presently, there is no standardiza-
tion or code-sharing across hospitals in any country, even if the
hospitals keep electronic health records. It was clearly shown that
this problem must be addressed by delivering standard informa-
tion technology (IT) programs and standards for data collection
in a form that is compatible with LSDBs.
Correspondence to: Heather J. Howard, Genomic Disorders Research Centre, Level
2, 161 Barry Street, Carlton South, 3053, Victoria, Australia. E-mail:
Myles Axton highlighted the need for both peer review and
microattribution as ways to provide incentives for locus annota-
tion. He also spoke about the challenges journals face in giving
proper attribution to the various roles of a rapidly increasing
number of consortium authors. To give variome contributors
appropriate credit for data generation and curation, more use can
be made of publisher metadata that identify author affiliations
and roles, but perhaps publishers need to develop tools to make it
easier for authors and copy editors to enter these data rapidly and
Publication of mutation data in a conventional way is becoming
more and more difficult. Robert Hoffmann has developed
WikiGenes [Hoffmann, 2008] to overcome this problem. This
Wiki format is now available online at and is
taking submissions. These submissions are open to debate and
refinement—this aspect of the process was discussed at length
with some delegates expressing apprehension of the ability to
change the text and many other thinking that this would bring a
higher degree of scrutiny of the published data. Also the
eventuality of extending this project into a PubMed-certified
resource, which would involve the organization of peer review and
editorial scrutiny through the HVP and HGVS, was discussed.
Richard Cotton presented a presentation sent by Leslie
Biesecker, who was unable to attend the meeting. This presenta-
tion covered the area of clinical nomenclature for malformations.
It was concluded that, to achieve consistency within the journals,
author participation would be needed as the resources of the
journals would be stretched.
Sean Tavtigian explained the work being done to create
standards for unclassified variants (UVs), particularly in the
BRCA genes. A multi-component classification algorithm is being
developed and if it is to become widely adopted, standards need to
be developed. This algorithm may not be completely perfect, but
with using this system pathogenicity will be more accurately
Sylvie Tuffery-Giraud illustrated the very impressive initiative
undertaken in France, where they have collected into a French
Duchenne muscular dystrophy (DMD) registry all mutations
identified by the diagnostic laboratories in French DMD and
BMD cases [Tuffery-Giraud et al., 2009]. They employed clinicians
full time for 3 years to go back and enter clinical records from the
clinician’s written notes. This work is very comprehensive and will
be of great assistance in research into muscular dystrophy. Quality
control was an issue, as many mistakes where found when they
interrogated the literature. Also, the accuracy of the molecular
data is greatly dependent on the techniques used at the time of the
diagnosis. This database will be an excellent model for global
registries and data sets. It will be used for diagnostics and will be
useful for data exchange with global database such as the one
developed within the TREAT-NMD European network
The meeting presenters and attendees agreed to the following;
there is a need for improved clinical ontology and prediction of
variants; standards for UVs are being developed but patient IDs
need to be considered; a suggested hierarchy of IDs; and consent
from families is critical.
The next major meeting of the HVP will be held in Paris 10 to
14 May, 2010 at United Nations Educational, Scientific, and
Cultural Organization (UNESCO). The meeting aims to formally
discuss the next steps to be taken and planned for the project
particularly surrounding ‘‘Implementation and Integration’’ and
aims to determine the major ways in which the recommendations
and actions from the first meetings can be best implemented in a
global collaborative context to prepare the systems necessary to
routinely and systematically gather the deluge of variations in
genes causing disease now being discovered. Meeting Website: 5Paris.
Antonarakis SE, Nomenclature Working Group. 1998. Recommendations for a
nomenclature system for human gene mutations. Hum Mutat 11:1–3.
Brookes AJ, Lehvaslaiho H, Muilu J, Shigemoto Y, Oroguchi T, Tomiki T, Mukaiyama
A, Konagaya A, Kojima T, Inoue I, Kuroda M, Mizushima H, Thorisson GA,
Dash D, Rajeevan H, Darlison MW, Woon M, Fredman D, Smith AV, Senger M,
Naito K, Sugawara H. 2009. The phenotype and genotype experiment object
model (PaGE-OM): a robust data structure for information related to DNA
variation. Hum Mutat 30:968–977.
Hoffmann R. 2008. A wiki for the life sciences where authorship matters. Nat Genet
Tuffery-Giraud S, Beroud C, Leturcq F, Yaou RB, Hamroun D, Michel-Calemard L,
Moizard MP, Bernard R, Cossee M, Boisseau P, Blayau M, Creveaux I,
Guiochon-Mantel A, de Martinville B, Philippe C, Monnier N, Bieth E,
Khau Van Kien P, Desmet FO, Humbertclaude V, Kaplan JC, Chelly J,
Claustres M. 2009. Genotype-phenotype analysis in 2,405 patients with a
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HUMAN MUTATION, Vol. 31, No. 3, 366– 367, 2010 367
    • "Human Genome Variation Society (HGVS) nomenclature is widely used for naming variations [10], however additional systematics would be needed. HGVS and Human Variome Project (HVP) have released a number of recommendations [11] , also for increased systematics, including recommendation to use VariO annotations [12]. The recent recommendations for LSDB establishment and curation emphasize the importance of systematics [13,14]. "
    [Show abstract] [Hide abstract] ABSTRACT: Systematic representation of information related to genetic and non-genetic variations is required to allow large scale studies, data mining and data integration, and to make it possible to reveal novel relationships between genotype and phenotype. Although lots of variation data is available it is often difficult to use due to lack of systematics. A novel ontology, Variation Ontology (VariO, was developed for annotation of effects, consequences and mechanisms of variations. In this article instructions are provided on how VariO annotations are made. The major levels for description are the three molecules, namely DNA, RNA and protein. They are further divided to four major sublevels: variation type, function, structure, and property, and further up to eight sublevels. VariO annotation summarizes existing knowledge about a variation and its effects and formalizes it so that computational analyses are efficient. The annotations should be made on as many levels as possible. VariO annotations are made in reference to normal states, which vary for each data item including e.g. reference sequences, wild type properties, and activities. Detailed instructions together with examples are provided to indicate how VariO can be used for annotation of variations and their effects. A dedicated tool has been developed for annotation and will be further developed to cover also evidence for the annotations. VariO is suitable for annotation of data in many types of databases. As several different kinds of databases are in a process of adapting VariO annotations it is important to have guidelines to guarantee consistent annotation.
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    • "•HVP (Human Variome Project):[58] "
    [Show abstract] [Hide abstract] ABSTRACT: The influence of resident gut microbes on xenobiotic metabolism has been investigated at different levels throughout the past five decades. However, with the advance in sequencing and pyrotagging technologies, addressing the influence of microbes on xenobiotics had to evolve from assessing direct metabolic effects on toxins and botanicals by conventional culture-based techniques to elucidating the role of community composition on drugs metabolic profiles through DNA sequence-based phylogeny and metagenomics. Following the completion of the Human Genome Project, the rapid, substantial growth of the Human Microbiome Project (HMP) opens new horizons for studying how microbiome compositional and functional variations affect drug action, fate, and toxicity (pharmacomicrobiomics), notably in the human gut. The HMP continues to characterize the microbial communities associated with the human gut, determine whether there is a common gut microbiome profile shared among healthy humans, and investigate the effect of its alterations on health. Here, we offer a glimpse into the known effects of the gut microbiota on xenobiotic metabolism, with emphasis on cases where microbiome variations lead to different therapeutic outcomes. We discuss a few examples representing how the microbiome interacts with human metabolic enzymes in the liver and intestine. In addition, we attempt to envisage a roadmap for the future implications of the HMP on therapeutics and personalized medicine.
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  • [Show abstract] [Hide abstract] ABSTRACT: SPOT (, the SNP prioritization online tool, is a web site for integrating biological databases into the prioritization of single nucleotide polymorphisms (SNPs) for further study after a genome-wide association study (GWAS). Typically, the next step after a GWAS is to genotype the top signals in an independent replication sample. Investigators will often incorporate information from biological databases so that biologically relevant SNPs, such as those in genes related to the phenotype or with potentially non-neutral effects on gene expression such as a splice sites, are given higher priority. We recently introduced the genomic information network (GIN) method for systematically implementing this kind of strategy. The SPOT web site allows users to upload a list of SNPs and GWAS P-values and returns a prioritized list of SNPs using the GIN method. Users can specify candidate genes or genomic regions with custom levels of prioritization. The results can be downloaded or viewed in the browser where users can interactively explore the details of each SNP, including graphical representations of the GIN method. For investigators interested in incorporating biological databases into a post-GWAS SNP selection strategy, the SPOT web tool is an easily implemented and flexible solution.
    Full-text · Article · Jul 2010
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