LAUSR

More than 300 distinct pathogenic variants have been reported in the ABCC6 gene [1]. Most of these variants are gathered in the public ABCC6 variants database (https://data bases.lovd.nl/shared/genes/ABCC6). These include missense, nonsense, frameshift, splice-site single-nucleotide variants (SNVs), and small deletions/insertions. In addition, large deletions or duplications of all or part of the gene are also frequently identified. Pathogenic variants are responsible for a partial or complete loss-of-function. Most variants are private, although two recurrent variants have been described. The SNV c.3421 C> T, p.(Arg1141Ter) is found with a prevalence of 25% in various ethnic backgrounds, and a large deletion of >16 kb encompassing exons 23–29 (c.2996–1724_4209–478del, also called “del23–29”) has a prevalence of 28% in Americans of European descent [2] and 11% in Caucasians [1]. Few other variants are found with a low level of recurrence. Causative variants are distributed throughout the gene, but two intracellular domains are significantly enriched with missense variants: the eighth intracellular loop and the nucleotide binding fold [1]. Polymorphic variants are listed in the dbSNP Database (http://www.ncbi.nlm.nih.gov/snp/), the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/), and in the Genome Aggregation Database (http://gnomad. broadinstitute.org). Please note that the abovementioned databases include pathogenic variants.