ClinVar Miner

Submissions for variant NM_000046.5(ARSB):c.1450A>G (p.Arg484Gly)

gnomAD frequency: 0.00005  dbSNP: rs201101343
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine RCV000169649 SCV000221172 likely pathogenic Mucopolysaccharidosis type 6 2014-03-03 criteria provided, single submitter clinical testing The Arg484Gly variant in ARSB has been reported in a patient with mucopolysaccharidosis type VI who also carried a pathogenic variant in trans (compound heterozygous) (Karageorgos et al, 2004). The Arg484Gly variant has been identified in 0.046% (1/2178) of the 1000 Genomes population. However, the presence of this variant in trans configuration with a reported pathogenic variant in an individual with clinical features of mucopolysaccharidosis type VI, increases the likelihood that the Arg484Gly variant is pathogenic. In addition, ARSB protein was not detected by an immunologic quantification assay supporting a deleterious impact to protein function (Karageorgos et al, 2004). In summary, the Arg484Gly variant is likely pathogenic for mucopolysaccharidosis type VI in a recessive manner.
Laboratory of Diagnosis and Therapy of Lysosomal Disorders,University of Padova RCV000169649 SCV000802998 uncertain significance Mucopolysaccharidosis type 6 2018-01-01 criteria provided, single submitter curation Very low frequency in GnomAD(PM2)
Invitae RCV000169649 SCV002249305 likely pathogenic Mucopolysaccharidosis type 6 2021-12-03 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 484 of the ARSB protein (p.Arg484Gly). This variant is present in population databases (rs201101343, gnomAD 0.01%). This missense change has been observed in individual(s) with mucopolysaccharidosis type VI (PMID: 14974081). ClinVar contains an entry for this variant (Variation ID: 189224). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ARSB protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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