The Alport syndrome COL4A5 variant database

Abstract

Alport Syndrome is a progressive renal disease with cochlear and ocular involvement. The most common form (~80%) is inherited in an X-linked pattern. X-linked Alport Syndrome (XLAS) is caused by mutations in the type IV collagen alpha chain 5 (COL4A5). We have developed a curated disease-specific database containing reported sequence variants in COL4A5. Currently the database archives a total of 520 sequence variants, verified for their position within the COL4A5 gene and named following standard nomenclature. Sequence variants are reported with accompanying information on protein effect, classification of mutation vs. polymorphism, mutation type based on the first description in the literature, and links to pertinent publications. In addition, features of this database include disease information, relevant links for Alport syndrome literature, reference sequence information, and ability to query by various criteria. On-line submission for novel gene variants or updating information on existing database entries is also possible. This free online scientific resource was developed with the clinical laboratory in mind to serve as a reference and repository for COL4A5 variants.

A mouse Col4a4 mutation causing Alport glomerulosclerosis with abnormal collagen α3α4α5(IV) trimers

“…24,25 These mice will therefore be useful for better understanding why the collagens are nonfunctional and whether development of specific therapies might be feasible for this class of patients. It is worth noting here that 17% of entries in the Alport Syndrome COL4A5 Variant Database 26 (http://www.arup.utah.edu/database/ALPORT/ALPORT_welcome.php) are splice site mutations, and there is a recent report of two pathogenic splice site mutations in human COL4A4 that affect the first base (G) of introns 22 and 28, respectively. 27 …”

Evidence of digenic inheritance in Alport syndrome

“…To determine whether the identified sequence variants were novel or had been previously reported, we searched in the dbSNP database (http://www.ncbi.nlm.nih.gov/projects/SNP/), the Human Gene Mutation Database (http://www.hgmd.cf.ac.uk/ac/index.php),29 the Leiden Open Variation Database V.2.0 Build 35 (https://grenada.lumc.nl/LOVD2/COL4A/variants.php?select_db=COL4A3&action=search_all&search_MutCol=%3E) and the ALPORT ( COL4A5 ) database (http://www.arup.utah.edu/database/ALPORT/ALPORT_display.php?sort=2#alport; last update: October 2013) 30…”

Collagen IV diseases: A focus on the glomerular basement membrane in Alport syndrome

“…An up to date summary of the mutations that cause Alport syndrome can be found in the Leiden Open Variant Database which is accessible at http://www.lovd.nl/3.0/home. While there are no mutational “hot spots” it is notable that there is indeed an association between the severity of the mutation and the severity of the disease [8,9]. Missense mutations that result in glycine substitutions are generally associated with a less severe form of the disease, while out of frame deletions, stop codons, and other mutations that result in chain termination are generally associated with the more severe phenotypes.…”