LOVD v.2.0: The Next Generation in Gene Variant Databases
Ivo F. A. C. Fokkema,yPeter E. M. Taschner,?yGerard C. P. Schaafsma, J. Celli,
Jeroen F. J. Laros, and Johan T. den Dunnen
Center of Human and Clinical Genetics, Department of Human Genetics, Leiden University Medical Center, Leiden, Nederland
For the HVP Bioinformatics Special Issue
Received 12 October 2010; accepted revised manuscript 14 December 2010.
Published online 22 February 2011 in Wiley Online Library (www.wiley.com/humanmutation). DOI 10.1002/humu.21438
ABSTRACT: Locus-Specific DataBases (LSDBs) store
information on gene sequence variation associated with
human phenotypes and are frequently used as a reference
by researchers and clinicians. We developed the Leiden
Open-source Variation Database (LOVD) as a platform-
independent Web-based LSDB-in-a-Box package. LOVD
was designed to be easy to set up and maintain and follows
the Human Genome Variation Society (HGVS) recom-
mendations. Here we describe LOVD v.2.0, which adds
enhanced flexibility and functionality and has the capacity
to store sequence variants in multiple genes per patient.
To reduce redundancy, patient and sequence variant data
are stored in separate tables. Tables are linked to generate
connections between sequence variant data for each gene
and every patient. The dynamic structure allows database
managers to add custom columns. The database structure
supports fast queries and allows storage of sequence
variants from high-throughput sequence analysis, as
demonstrated by the X-chromosomal Mental Retardation
LOVD installation. LOVD contains measures to ensure
database security from unauthorized access. Currently,
the LOVD Website (http://www.LOVD.nl/) lists 71 public
LOVD installations hosting 3,294 gene variant databases
with 199,000 variants in 84,000 patients. To promote
LSDB standardization and thereby database interoper-
ability, we offer free server space and help to establish an
LSDB on our Leiden server.
Hum Mutat 32:557–563, 2011. & 2011 Wiley-Liss, Inc.
KEY WORDS: LSDB;
The Leiden Open source Variation Database (LOVD), a freely
available Web-based software for the collection, display, and
curation of DNA variants in locus-specific databases (LSDBs) was
developed following the LSDB-in-a-box concept [Fokkema et al.,
2005]. The basic design criteria included a Web-based database
system, based on freely available open source software, easy to use
and install by noncomputer experts. Curators should be able to
install a database system ‘‘out of the box’’ without complicated
platform-specific programming or configuration steps. The LOVD
system has been designed to comply with the guidelines and
recommendations regarding content, design, and deployment of
sequence variant databases developed by the HUGO Mutation
Database Initiative, the Human Genome Variation Society
(HGVS, http://www.hgvs.org/), and the Human Variome Project
[Cotton et al., 2008; Scriver, 2000; Scriver et al., 1999].
The modular LOVD design provides the flexibility necessary to
cope with the specific interests of the users of patient-centered,
sequence variant-centered, disease-centered, and protein-centered
databases. Since the original LOVD release, updates with new
functional enhancements and bug fixes have been released
regularly. Starting with the Leiden Muscular Dystrophy pages
(http://www.DMD.nl/), many LSDBs have changed to an LOVD
format. Because these transfers contribute to LSDB standardiza-
tion and facilitate easy automated data retrieval, other LSDB
curators are tempted to follow this example by using LOVD or
other general software (UMD [Be ´roud et al., 2000] or Mutbase
[Riikonen and Vihinen, 1999]). LOVD users have requested new
features, for example, to allow curators to design different custom
column sets to be used per gene database. To meet these requests,
the database structure of LOVD v.2.0 has been redesigned without
changing the original specifications [Fokkema et al., 2005]. This
new design includes measures to prevent unauthorized data
modification, to enhance data safety, and to repel Web attacks.
Materials and Methods
LOVD v.2.0 System Requirements, Database Installation,
The LOVD v.2.0 software is platform-independent. Use on a
Web server requires the installation of the following freely
available Open Source software: an HTTP Web server (e.g.,
Apache, http://www.apache.org), the PHP scripting language
v.4.2.0 and up (http://www.php.net), and the MySQL database
package v.3.23.33 and up (http://www.mysql.com). This software
is installed on the servers of most (commercial) hosting providers.
Ready-to-install binaries are available for most operating systems
from the links provided above. The LOVD v.2.0 software is freely
available from http://www.LOVD.nl. Detailed information about
the installation, configuration, and upgrades is provided under the
Documentation tab on the LOVD home page, which also provides
access to the manual. Simple LOVD test installations (including
Apache, PHP, and MySQL) can be set up on local Windows
& 2011 WILEY-LISS, INC.
Contract grant sponsor: The European Community’s Seventh Framework
Programme; Contract grant number: FP7/2007-2013, under grant agreement no.
200754—the GEN2PHEN project.
Additional Supporting Information may be found in the online version of this article.
yBoth authors contributed equally.
?Correspondence to: Peter E. M. Taschner, Department of Human Genetics S-4-P,
Center for Human and Clinical Genetics, Leiden University Medical Center,
Albinusdreef 2, P.O. Box 9600, 2300RC Leiden, Nederland. E-mail: P.Taschner@lumc.nl
computers by downloading the CD image from the Website,
burning the install CD, and inserting it into the computer. After
following the instructions on the screen, LOVD can be set up in
just a few minutes. Installing one of the regular updates only
requires the old files to be overwritten on the server. The database
backend will be upgraded automatically after the first activity by
the database administrator, manager, or curator.
LOVD Extension Modules and Scripts
The modular design concept allows simple functionality
extensions using specific modules. Three standard modules are
prepackaged and installed automatically during LOVD v.2.0
installation and can be turned on and off on demand:
1. Mutalyzer nomenclature checker module—modifies the variant
submission form to send the DNA change description and the
reference sequence accession and version number to a remote
server (http://www.mutalyzer.nl) running the new version 2 of the
Mutalyzer software [Wildeman et al., 2008]. This tool performs
an automatic check for compliance to the HGVS sequence
variant nomenclature guidelines [Den Dunnen and Antonarakis,
2000; Den Dunnen and Paalman, 2003] to guarantee error-free
entry of the sequence variants submitted. The Mutalyzer output
containing the checked description and predicted effects at
protein level will be displayed in a new window.
2. ShowMaxDBID—modifies the variant submission form for
curators by presenting the first free value for the DB-ID field.
3. reCAPTCHA—modifies the submitter registration form to
include an image displaying text that only humans can read.
New submitters are required to type the words in the image to
prevent fake registrations by spam bots.
Additional functionality is provided by other scripts. The
GenBank File Uploader script allows curators to import custom
reference sequences in GenBank format for checks with Mutalyzer
and for use in the Reference Sequence Parser. The latter script
helps curators to generate reference sequences in GenBank format
with the appropriate transcript and protein annotation needed by
Mutalyzer. The Reading Frame Checker uses information about
the first and last exon deleted or duplicated in a gene to return the
correct description of the change on DNA level as well as the
predicted effect on protein level (in- or out-of-frame).
In the new database structure, patient data and sequence variant
data are stored in separate tables to allow the creation of links
between sequence variants in different genes and the same patient
(see the LOVD v.2.0 database scheme in Supp. Fig. S1). This is
particularly useful for oligogenic disorders, in which more than
one gene has to be inactivated before manifestation, for example,
Bardet-Biedl syndrome [Beales et al., 2003]. Data redundancy is
reduced by storing the results of multiple mutation screens in one
database which increases flexibility by allowing variant overviews
per patient. System-wide views of all variant and patient
information of a certain origin are supported if the patient
geographic or ethnic origin columns have been enabled (see below).
The LOVD software was designed to withstand all known types
of attacks on Web-based database systems. These include: brute-
forcing account passwords, SQL injection, XSS attacks, local and
remote file inclusion, session hijacking and fixation, and network
sniffing. Furthermore, the source code was checked using different
security audit programs: CodeSecureTM(Armorize Technologies,
Santa Clara, CA) and Spike PHP Security Audit (http://
developer.spikesource.com/projects/phpsecaudit), partially in co-
operation with security specialists of the National Center for
Biotechnology Information (NCBI). LOVD has two options to
secure the personal curator, manager or database administrator
accounts against password guessing. Each user can restrict access
to their account to a certain IP address, an IP address range, or a
list of these. Attempts to access the account from another computer
will result in an error, even if the password is correct. Furthermore,
an account will be locked by default after three failed log in
attempts. Accounts can only be unlocked by a user of a higher level
or, if enabled, by requesting LOVD to send a new password to the
user’s registered email address. LOVD logs all access attempts,
including IP addresses from which they were made.
To protect against unauthorized modification of data, users
need to confirm important data manipulations by entering their
password before changes are saved. This prevents others, who use
a computer where a user is logged in, from making modifications.
If the server supports the secure socket layer (SSL) protocol for
encryption, LOVD can be configured to force the use of SSL to
secure the transfer of passwords or sensitive patient data over
insecure networks. The transition from normal HTTP to an SSL
connection will not be noticed when configured properly.
Results and Discussion
The LOVD User Interface
The homepage of a gene variant database displays general
information about the gene and the database structure, and includes
links to other sites of interest (e.g., OMIM, Entrez Gene, HGMD,
etc.) as recommended by Claustres et al. . From here, users
can access the allelic variant information and search the database. As
shown with the Lamin A/C (LMNA) example from the Leiden
Muscular Dystrophy pages (http://www.LOVD.nl/LMNA) a gene
home page contains several new features (Fig. 1). The uppermost
section of the page shows a green arrow, which allows users to select
the gene of interest from the specific LOVD installation. To improve
accreditation of the work performed, the curator’s name is now
displayed below the name of the gene. In compliance with the latest
HGVS guidelines, the bottom of the homepage contains a copyright
statement and a disclaimer. Tabs allow the user to search variants,
view a list of submitters with contact information, submit new
variants, and access the manual. Links in the top right corner
provide access to information on the current status of the installation
(e.g., the number of LSDBs on the server and the total number of
sequence variants per database), submitter registration and the log in
screen. A new feature of the general information section is a link to
all PubMed references covered by the database entries.
The graphical display options contain links to the UCSC and
Ensembl genome browsers and the NCBI sequence viewer,
showing the stored variants in custom tracks. Summary tables
show statistics on the percentages of variants per exon or the
number of variants per bp per exon. This can reveal interesting
information on the distribution of variants in the gene, such as
specific hotspots. Unique for LOVD are separate diagrams
showing the distribution and the numbers of the different variant
types (substitutions, deletions, insertions, etc.) at the DNA, RNA,
and protein levels, calculated automatically from the variant
HUMAN MUTATION, Vol. 32, No. 5, 557–563, 2011
descriptions. The Reading-frame checker module is an additional
feature, which can predict the effect of whole-exon changes on the
reading frame (frame shifting or in frame). A news feed which
automatically notifies subscribers of changes and additions to a
specific gene or the complete database has been included.
Searching and Viewing Table Information
The ‘‘Search the database’’ section has been extended with two
new options. The first is a search on the geographic or ethnic
origin of the patient or the location of the laboratory reporting the
variant. The latter feature allows collaborating labs to list all their
contributions on their homepage, improving the accreditation
received for the work performed. On the issue of country- or
ethnicity-specific databases versus central databases, it should be
noted that these additions diminish the need for separate
databases. Separate databases will disperse data, reduce options
to get a simple and up-to-date overview, and may lead to
confusion if a patient is for example from a mixed background.
There are a variety of options to search and customize the user
interface. LOVD can contain both public and nonpublic data. The
second option ‘‘Search through hidden entries’’ can be enabled by
curators to allow queries of restricted data. This search does not
return the data itself, but the number of records matching the
query. After clicking the Variants tab, the ‘‘Unique sequence
variants’’ overview lists all the variant information recommended
by the HGVS. Users can adapt the display to their preference by
hiding columns and by sorting data on any column of interest
(Fig. 2). Search boxes below the column headings support more
detailed queries with Boolean operator symbols in any combination
desired. Because the Boolean operators AND, OR, and NOTmay be
part of search strings, LOVD uses a space for AND, the pipe symbol
| for OR and the exclamation mark ! for NOT. Boolean operator
symbols should not be surrounded by spaces, for example, using
Brazil|Canada in the Geographic Origin field of the LMNA database
will return variants in patients from Brazil or Canada.
Published variants can be linked to PubMed using their PubMed
ID, while the CustomLinks option facilitates direct linking to full text
papers using their DOI. For variants present in OMIM [Hamosh
et al., 2005], we provide a link in the Reference field of the entry.
Variants present in dbSNP [Sherry et al., 2001] are entered as an
independent record containing the DNA variant description, the
predicted protein change, a link to dbSNP (Reference field) and the
range of variant frequencies when reported in dbSNP (Frequency
field). All dbSNP entries are linked (per gene) to one hypothetical
patient called ‘‘dbSNP.’’ This allows easy retrieval of dbSNPentries by
searching the Reference field for ‘‘dbSNP’’ or just clicking one entry.
Data on variants found in animal models (including total gene
knock outs and deletion or substitution variants) are also connected
to a hypothetical patient (Patient-ID: ‘‘animal’’). For example, mouse
models carrying SGCA gene variants can be retrieved by searching
the Variant remarks field for ‘‘mouse’’ (See http://www.lovd.nl/
SGCA). The mouse variant is described at DNA, RNA, and protein
level using the human reference sequence numbering. To clearly
discriminate it from a true variant found in human, the description
follows the HGVS rules for predicted effects and uncertain positions,
which require the change to be shown in parentheses, for example,
c.(1234G4T). The Remarks field clearly states the organism inwhich
the variant was found; the Pathogenicity field is where functional
c.(1234G4T) is also used to list variants in pseudogenes that may
be observed with nonspecific detection methods (e.g., nonunique
PCR products). Again, the Remarks field is used to mention potential
problems and to indicate the pseudogene. Searching for ‘‘c.(‘‘ will
retrieve all these cases. Any available data on the functional analysis of
gene variants are linked to a hypothetical patient (Patient-ID: ‘‘in
vitro’’). Each specific variant is described (DNA, RNA, Protein,
Reference, etc.) with details of the test performed and the results
obtained (Remarks field), connected to a classification of the variants
functional consequences (Pathogenicity field).
Combination of variants are stored and displayed per patient
(and per chromosome) (Fig. 3). To facilitate the interpretation of
variant data in relation with disease, specific descriptions can be
used to present information about the chromosome, which does
not carry the variant. These descriptions are: c.5(‘‘normal 2nd
chromosome’’), c.0 (‘‘no paternal X-chromosome’’), and c.?
(‘‘unknown variant in 2nd chromosome’’). In patients affected
by a recessive disease, one thus expects to identify one pathogenic
variant for each of the two chromosomes. To highlight those cases
where thus far variants in only one chromosome where detected,
we add c.? for the other chromosome, with the remark field stating
‘‘unknown variant 2nd chromosome.’’ For dominant diseases, the
second chromosome is listed as c.5, with the remark ‘‘normal 2nd
chromosome.’’ In the case of X-linked recessive diseases, the second
chromosome is listed as c.0 (‘‘no paternal X-chromosome’’) in
males and as c.5in females. We have noted that this increases the
on the Webpage provide access to the sequence variant information in
the LMNA database or to external resources containing data about the
LMNA gene and associated diseases. [Color figures can be viewed in
the online issue, which is available at www.wiley.com/humanmutation.]
The LMNA database gene homepage. The underlined links
HUMAN MUTATION, Vol. 32, No. 5, 557–563, 2011
awareness of nonexpert users, for example, carrier females in
Duchenne Muscular Dystrophy, explaining why they remain
unaffected despite carrying a nonsense variant in their genome.
The c.5, c.0 and c.? variants receive database ID_00000 and are
removed from the summary listings by the LOVD software.
Clicking on a variant will open a detailed view showing all entries
carrying that variant, including patient and pathogenicity informa-
tion. Columns can contain links to additional information (e.g.,
pedigree structure, growth curve, functional assay data, etc.). Access
to this information can be unrestricted (public internet servers) or
restricted (local servers or even the computer of the submitter
only). One purpose of this option is to indicate that such
information is present without making it publicly available.
Selecting and clicking a specific row will open a detailed view
showing all details per patient. Standard patient data fields include
disease, geographic origin, ethnic origin, gender, and the name of
the submitter. This overview also shows the details of the selected
variant as well as a table with all other variants identified in the
same and other genes of the same patient. Finally, graphical displays
of the variants in several genome browsers (Ensembl [Flicek et al.,
The variant listing of the patient may contain additional variants in the same gene or in other genes in the same LOVD installation. [Color figures
can be viewed in the online issue, which is available at www.wiley.com/humanmutation.]
Patient data associated with CAPN3 variant c.984C4A. Data were accessed by clicking the c.984C4A information in Figure 2.
analysis. The underlined links allow the user to view additional information about multiple database entries for the same variant or direct access
to reference information in PubMed or OMIM. Several columns have been hidden from view. [Color figures can be viewed in the online issue,
which is available at www.wiley.com/humanmutation.]
CAPN3 sequence variants displayed after a full database search for exon 7 allelic variants detected by single strand conformation
HUMAN MUTATION, Vol. 32, No. 5, 557–563, 2011
2010], UCSC [Kent et al., 2002], NCBI Sequence Viewer (http://
www.ncbi.nlm.nih.gov/projects/sviewer/)) are provided.
Sequence Variant Submission
The Web interface is publicly available and can be freely searched,
but other activities, including sequence variant submission, require
prior registration. Submitters can view, list, and edit all their
records, add new patients or new variants to existing patients and
generate personal submitted variant overviews to disseminate their
work. When enabled, the sequence variant submission form
supports checks of the variant description using the Mutalyzer
module [Wildeman et al., 2008] (Fig. 4). When submitters add new
information, the curators receive an e-mail copy as reminder and
the entries will be nonpublic until approved by a curator.
Database Curation and Management
After curator approval, new variants are automatically displayed
as public entries and their information is included in all linked
Web pages. To support submission of larger datasets, curators can
import tab-delimited data files provided by submitters or from
previous LSDB versions. LOVD provides tools to quickly search,
retrieve, and simultaneously change sets of entries. The search
overview and simple pattern matching on specified fields or
combinations of fields helps to select entries for editing. LOVD
now includes a find and replace functionality, as well as a ‘‘copy
column’’ feature facilitating simple database reformatting. More
details about database customization by curators and database
administrators can be found in Supp. Information S2.
Locus-Specific Databases Based Upon LOVD
Since the release and publication of LOVD [Fokkema et al., 2005],
many curators have moved their database or static PDF and HTML
files into an LOVD format. The use of LOVD has grown from the 17
mutation databases with 7,485 variants kept at the Leiden Muscular
Dystrophy pages (http://www.DMD.nl/, February 18, 2005) to 71
public LOVD installations hosting 3,294 gene databases containing
199,000 variants in 84,000 patients (December 16, 2010). An overview
of genes covered by public variant databases is available on the central
LOVD server (see http://www.LOVD.nl for the current figures).
Databases hosted on the Leiden servers are included by default.
Database administrators who have set up their own online installation
can activate the ‘‘share option’’ allowing communication with the
central LOVD server. The data shared includes the name and location
of the database, the names and number of the genes, the LOVD
version, the number of (unique) variants and curator details. We have
exploited this feature, together with the list of LSDBs provided by the
HGVS, to create the URL http://geneID.lovd.nl (e.g., FKRP.lovd.nl),
which allows users to be transferred directly to the database for the
‘‘geneID’’ gene (or a list of LSDBs when more than one exists).
With the support of the EU FP7-funded Gen2Phen project, we
assist curators in the transfer of their LSDBs to a LOVD format. An
example is the Mental Retardation database project (http://
www.lovd.nl/MR), for which we created over 500 LSDBs for the X
chromosome genes in a single installation in order to store the results
of a large-scale resequencing study in patients with X-linked mental
retardation [Tarpey et al., 2009]. Because individual access can be
restricted to a subset of genes, large groups of curators can easily work
together in a single installation without interfering with other users.
The standard installation comes with limited graphical display
tools. This is due to the maximal flexibility we allow curators in
extending LOVD with custom columns, making it difficult to
automatically generate graphical displays. We have implemented
methods to display data using the custom track option of the
Ensembl and UCSC genome browsers and NCBI Sequence Viewer.
window. The protein variant description is shown between parentheses to indicate that it was derived by translation of the open reading frame
of the reference sequence. [Color figures can be viewed in the online issue, which is available at www.wiley.com/humanmutation.]
Submission of an LMNA variant checked via the Mutalyzer module. The results of the Mutalyzer 2 check are displayed in a new
HUMAN MUTATION, Vol. 32, No. 5, 557–563, 2011
To accomplish this, LOVD stores chromosomal coordinates for all
variants and uses this to transfer it to BED format. All variants will
be shown relative to the annotation tracks in the genome browser.
This allows the user to see local features, including known
transcripts, conservation, dbSNP, structural variants, and flanking
genes. In addition, users can use the tools provided by the genome
browser to download (part) of the sequence, design PCR primers,
etc. A similar display for individual variants is available by clicking
the UCSC genome browser link in the detailed variant view.
Programmatic Queries of LOVD Installations
A new feature is an Application Programming Interface (API),
which supports searches performed by computer programs. The
API supports searching for genes based on gene symbol,
chromosomal position or region and, per gene, for variants based
on chromosomal positions or regions, positions or regions in the
transcript, or DNA change description (see search formats in
Supp. Information S3).
Data Sharing, Import, and Export
The flexibility achieved by creating custom columns is in itself
detrimental for standardization. To bypass this, we have
implemented the option to share custom column settings with
another LOVD installation. To support standardization, column
data can be exported and imported into other installations.
Patient and variant data can also be easily imported and exported.
LOVD supports multiple-gene data downloads for LSDB data
sharing with central repositories according to the HGVS
recommendations [Den Dunnen et al., 2009].
LOVD development is currently supported by the Gen2Phen
project, funded by an EU FP7 grant. Within Gen2Phen, a general
data model representing the data from genetic and genomic
databases is under development with the ultimate goal being the
development of a general data exchange format (see http://
www.gen2phen.org/ for more information). Implementation of the
Gen2Phen data model in database software will result in improved
mapping of data between databases using the same syntax. This
should increase their interoperability and improve automated data
retrieval and submission from different sources. Because the data
model includes all standard fields currently used in LOVD, UMD
[Be ´roud et al., 2000] and Mutbase [Riikonen and Vihinen, 1999]
database software, it should support data retrieval from these
systems through world-wide queries once they are registered in the
public gene variant database list. The LOVD query service can be
regarded as a step toward accomplishing one of the aims of the
Human Variome Project [Ring et al., 2006]: a central access point
for the retrieval of variants in all genes worldwide, saving
diagnostic laboratories, clinicians, and researchers considerable
amounts of time and money [Cotton et al., 2008].
The Gen2Phen data model will be implemented in the database
structure of LOVD v.3.0, which is currently under development
(see http://www.lovd.nl/3.0/ for more information). In addition to
gene, patient, and variant data objects, LOVD v.3.0 will contain
new disease, phenotype, and screening data objects to support
enhanced customization of phenotype and mutation screening
information in gene variant databases within a single installation
with more patient-centered, disease-centered, and protein-cen-
tered interests. Further improvement of interoperability will
require semantic standardization of the database contents. To
promote this, database software should support the use of
ontologies and controlled vocabularies at least in fields containing
information necessary for data exchange. The interoperability of
genetic and genomic variant databases will also benefit from
conversions of coding DNA positions used in LSDB variant
descriptions to chromosomal positions used in genomic variant
databases descriptions. Position conversions are part of the core
functionality of the Mutalyzer nomenclature checker. LOVD
already uses the new Mutalyzer 2 to calculate genomic positions
for variant display in genome browsers. This interaction will be
extended to handle position conversions in combination with a
standard HGVS nomenclature check. In addition, future versions
will use the reference sequence parsing capability of Mutalyzer 2.
As part of the Gen2Phen project, we have recently generated a
gene variant database for all genes linked to Mendelian disorders.
Although we are working on importing data from literature, at the
moment most of these databases are empty. Researchers with an
informal database or even simple lists of gene variants are invited
to contact us in order to upload these data. Similarly, this resource
is suitable for storage of data obtained from exome/genome
sequencing studies. In addition to gene variant data, these LSDBs
need guardians: experts willing to devote some of their time to
curate incoming data, promoting the database and uploading
available data. If you are interested in extending your CV with an
LSDB curatorship, please contact us. All feedback and efforts of
the user community in extending the capabilities of LOVD by
writing additional scripts are also warmly welcomed.
The authors specifically thank Raymond Dalgleish, and the many other
LOVD database curators for their feedback and support, and Jean-Pierre
Bayley for critically reading the manuscript.
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