SPRED1 database website
database can be found under Disease Databases on the ARUP Online Scientific Resource webpage http://www.arup.utah.edu/
or accessed directly by using the URL http://www.arup.utah.edu/database/SPRED1/SPRED1_welcome.php
. Navigation between the series of webpages can be done using the quick links as shown in . The SPRED1
“Home” webpage briefly describes Legius syndrome, phenotype, the database goals, reference sequences used, and gene sequencing tests available at ARUP Laboratories. The right frame of the page conveniently lists contact information for the appropriate experts involved in the database development and curation, including medical director, submissions, testing, and website administrator. The “Home” page also provides a graphic link to the SPRED1
gene topic hosted by the National Library of Medicine’s Genetics Home Reference (http://ghr.nlm.nih.gov/gene/SPRED1
Figure 1 Legius syndrome database display. (A) Quick links for navigation within the website for SPRED1 homepage, database display, links, and submission. (B) Main database display including a “live search” function for easy filtering to gene variants (more ...)
The SPRED1 “Links” webpage has hyperlinks to existing online resources for Legius syndrome and SPRED1, including Databases, Gene and Protein Links, Web Reviews, and Literature Reviews. Some of the resources listed here include Gene Reviews, Genetics Home Reference, OMIM, UniProt, Human Protein Reference Database (HPRD), and the SPRED1 reference sequences used for our database curation. Lastly, recent literature reviews from experts in this disease area are posted and updated as appropriate.
The SPRED1 database can be displayed and searched in its entirety by accessing the “Database” webpage shown in . The database contained 78 entries as of May 2011. The default database display is by genomic position of each sequence variant (5′ to 3′) within the SPRED1 gene. shows the database display columns of Location, Mutation Type, Nucleotide Change, Protein Change, Classification, Meets NIH NF1 Criteria, References, and Comments. Information in the Comments column () is available by placing the pointer over the comments icon. This information may further explain the data displayed for each entry. The database also has “live search” functionality, so that any term entered in the search box (e.g., exon, insertion, benign, or author name), will dynamically filter the displayed listing. Finally, clicking any column heading will sort (ascending and descending) the gene variant entries for redisplay.
The “Submissions” webpage is used for submission of novel SPRED1 sequence variants to the database or to update information for sequence variations currently archived in the database. Contact information is conveniently seen on the “Home” and “Links” pages. Requested information during submission includes gene variant location, mutation type, classification, nucleotide change, protein change, clinical significance, and contact information of the submitter. All submissions are received via autogenerated e-mail to the curators, and variant updates are added to the database quarterly.
Database display columns
SPRED1 sequence variation location and mutation type:
The Location column displays the exon or intron number for each SPRED1
gene variant. Mutation Type describes the biological event leading to the change in the DNA (relative to the reference sequence). Common types of variants include small deletions and insertions/duplications, missense, nonsense, splice-site, silent, and recently, large deletions (those equal to or larger than a single exon) that have been reported (Spencer et al. 2011
). Large duplications have not been reported in individuals with Legius syndrome. SPRED1
gene variant mutation types are graphically summarized in .
Dynamic graphical summary of (A) variant classification and (B) types of mutations found in the SPRED1 database.
The Nucleotide Change column displays the corresponding HGVS nomenclature (Den Dunnen and Antonarakis 2000
). For cDNA numbering in the Nucleotide Change column of the SPRED1
database, the first cDNA nucleotide (c.1) is the “A” of the ATG initiation (start) codon.
SPRED1 protein change:
For the Protein Change column, the single amino acid changes are listed in the database display. Where splice-site variants occur, only the genotype is listed, with the protein change indicated with a question mark.
Classification of pathogenicity:
In the Classification column, definitions for pathogenicity are Pathogenic, Suspected Pathogenic, Benign, Suspected Benign, or Uncertain. As is common practice, loss of function (LOF) mutations are assumed pathogenic, and the author’s classification for each variant was used.
Legius syndrome phenotype:
The phenotype associated with each variant is listed by author if the variant was reported more than once.
References and comments:
The final two columns of the database feature links to literature resources and genotype/phenotype findings of each individual variant. As displayed in , moving the cursor over the comments icon highlights a key feature and unique part of this online resource. Comments for each SPRED1 variant often contain additional information or evidence to support the classification designation and whether the patient meets NIH diagnostic criteria for a clinical diagnosis of NF1. Importantly, clinical details, such as age or other conditions, may be included. Sensitive and private patient information is never listed.
Currently, the database displays information and classification of 78 SPRED1 gene variants. However, this number is actively increasing as additional variants are described in the scientific literature and discovered in routine clinical testing and research laboratories. Pathogenic mutations detected during routine clinical testing of patient samples at ARUP Laboratories or those submitted by other laboratories will also be added to the database. As mentioned above, for variants included from the scientific literature, the database provides a linked reference to the PubMed abstract for each variant. Because the classification of each variant is directly based on evidence from the scientific literature, the link to PubMed is a very useful feature of this database. However, in cases where a variant has not yet been reported in the literature, the database provides the clinical and/or experimental, functional data suggestive of its classification. Laboratories and database users may also contact curators via e-mail or phone regarding database entries, additional references, or clarification of information posted on the site at any time.
summarizes the content of the SPRED1 database by variant classification and mutation types. Analysis of the different types of mutations currently contained in the database are provided, including deletion (16), large deletion (3), insertion/deletion (1), duplication (6), insertion (4), missense (23), nonsense (16), silent (4), intronic (4) and splice site effect (1).
Clinical significance of the database
Clinical and research laboratories that offer full gene analysis often encounter rare variants and must rely on the published literature or online resources to make informed decisions about the classification of the variant when reporting their findings. We developed this database to facilitate this decision-making process and assist those who interpret results and care for patients. A key feature of this database is the ease of access with which it provides pertinent gene variant information and the associated genotype-phenotype observations. In addition, the database is curated by individuals with expertise in molecular genetics and Legius syndrome, ensuring that all of the information contained in the archive is up to date and of sufficient scientific rigor. Finally, as this database is a publicly available resource, with no login or membership requirement, it serves as an ideal centralized resource to all laboratories offering SPRED1 gene analysis, as well as to genetic counselors or physicians treating patients.