ClinVar Genomic variation as it relates to human health

Variant summary: The NAGLU c.1597C>T (p.Arg533*) variant results in a premature termination codon, predicted to cause a truncated or absent NAGLU protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. Functional analysis shows that this variant escapes NMD (Mangas_2008). Thus, based on its location and effect, it is expected to delete a substantial part of Alpha-N-acetylglucosaminidase, C-terminal domain (residue 474 733) (InterPro). Truncations downstream of this position (e.g. p.Arg626Ter, c.1944dupG, etc.) have been reported in MPS IIIB patients and classified as pathogenic by the labs in ClinVar. This variant is absent in 114224 control chromosomes from ExAC. In literature, this variant has been reported in two Portuguese MPS IIIB patients: one patient with severe disease was homozygous for the variant and other patient with mild disease was compound heterozygous for this variant and R643C (Mangas_2008). Functional analysis using patient cells from the homozygote showed null enzymatic activity. Taken together, this variant is classified as Pathogenic.

The NAGLU c.1597C>T (p.Arg533Ter) variant is a stop-gained variant that is predicted to result in premature termination of the protein. The p.Arg533Ter variant has been reported in one study in which it was found in two individuals with mucopolysaccharidosis type III, specifically type IIIB, including in one who carried the variant in a homozygous state and one who carried the variant in a compound heterozygous state (Mangas et al. 2008). The p.Arg533Ter variant was absent from 50 unrelated controls and is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium in a region of good sequence coverage so the variant is presumed to be rare. Characterization of cell lines derived from the two patients showed significantly reduced mRNA levels and enzymatic activity (Mangas et al. 2008). Based on the evidence and the potential impact of stop-gained variants, the p.Arg533Ter variant is classified as likely pathogenic for mucopolysaccharidosis, type III. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

This sequence change creates a premature translational stop signal (p.Arg533*) in the NAGLU gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 211 amino acid(s) of the NAGLU protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 18218046). ClinVar contains an entry for this variant (Variation ID: 495784). For these reasons, this variant has been classified as Pathogenic.

The c.1597C>T (p.R533*) alteration, located in exon 6 (coding exon 6) of the NAGLU gene, consists of a C to T substitution at nucleotide position 1597. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 533. This alteration occurs at the 3' terminus of the NAGLU gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 28% (210/743 amino acids) of the protein. Premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This mutation has been reported in the homozygous and compound heterozygous states in patients with biochemically confirmed mucopolysaccharidosis type III. Patient cell lines demonstrated significantly decreased levels of mRNA and enzymatic activity (Mangas, 2008). Based on the available evidence, this alteration is classified as pathogenic.