ClinVar

Description

Variant summary: GALNS c.899-1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: four predict the variant abolishes a 3' acceptor site. At least one publication (Carraresi_2008) reported experimental evidence confirming this prediction, by demonstrating in patient derived fibroblasts that the variant results in two aberrantly spliced transcripts with exon 9 skipping (both causing a frame-shift, introducing a premature stop codon, however both mRNAs seemed to escape nonsense-mediated decay (NMD)). The variant allele was found at a frequency of 4e-06 in 248806 control chromosomes (gnomAD). c.899-1G>C has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (e.g. Carraresi_2008, Morrone_2014, Caciotti_2015). These data indicate that the variant is likely to be associated with disease. At least one publication also reported experimental evidence demonstrating an impact on protein function, i.e. showing that GALNS enzyme activity was completely absent in leukocytes derived from a patient homozygous for the variant of interest (Caciotti_2015). One ClinVar submitter (evaluation after 2014) has cited the variant and classified it as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.