ClinVar Miner

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

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
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.
Invitae RCV001238278 SCV001411079 pathogenic Mucopolysaccharidosis, MPS-III-B; Charcot-Marie-Tooth disease, axonal type 2V 2019-08-20 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the NAGLU gene (p.Arg533*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 211 amino acids of the NAGLU protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be homozygous or in combination with another NAGLU variant in individuals affected 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.
Department of Genetics,Sultan Qaboos University Hospital, Oman RCV000761492 SCV000891610 pathogenic Mucopolysaccharidosis, MPS-III-B 2017-12-30 no assertion criteria provided curation

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