ClinVar Miner

Submissions for variant NM_000263.4(NAGLU):c.1597C>T (p.Arg533Ter) (rs1244655820)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Department of Genetics,Sultan Qaboos University Hospital, Oman RCV000761492 SCV000891610 pathogenic Mucopolysaccharidosis, MPS-III-B 2017-12-30 no assertion criteria provided curation
Illumina Clinical Services Laboratory,Illumina RCV000761492 SCV000914766 likely pathogenic Mucopolysaccharidosis, MPS-III-B 2017-04-28 criteria provided, single submitter clinical testing 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.
Integrated Genetics/Laboratory Corporation of America RCV000589472 SCV000696366 pathogenic Sanfilippo syndrome 2016-12-23 criteria provided, single submitter clinical testing 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.

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