ClinVar

Description

Variant summary: HGSNAT c.-115_-101dup15 is located in the untranscribed region upstream of the HGSNAT gene. The variant allele was found at a frequency of 0.002 in 30350 control chromosomes (gnomAD). The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in HGSNAT causing Mucopolysaccharidosis Type IIIC (Sanfilippo Syndrome C) phenotype (0.001), suggesting that the variant might be benign. To our knowledge, no occurrence of c.-115_-101dup15 in individuals affected with Mucopolysaccharidosis Type IIIC (Sanfilippo Syndrome C) and no experimental evidence demonstrating its impact on protein function have been reported. HGSNAT transcription is driven by a TATA-less promoter whose key elements are contained within the 1054 bp region upstream of exon 1. Richtrova_2016 showed that "reduced reporter activities from promoter serial deletion constructs suggested strong regulatory elements at positions 101 to 20 bp and 1073 to 716 bp of the downstream initiation codon (DS-ATG)". Targeted mutagenesis of the first specificity protein 1-A (Sp1-A), located at -96 to -85 positions led to a 55% decrease of reporter activity. Thus, this confirms that Sp1 is important for regulation of the HGSNAT gene. This variant is located in close proximity to the Sp1-A binding site, thus it may interfere transcription. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No other clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly benign until more information becomes available.