ClinVar Miner

Submissions for variant NM_000046.5(ARSB):c.1507C>T (p.Gln503Ter)

dbSNP: rs771113472
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova RCV000677494 SCV000803004 likely pathogenic Mucopolysaccharidosis type 6 2018-01-01 criteria provided, single submitter curation Nonsense variant (PVS1); Very low frequency in ExAC (PM2)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000677494 SCV001572523 pathogenic Mucopolysaccharidosis type 6 2023-08-14 criteria provided, single submitter clinical testing Variant summary: ARSB c.1507C>T (p.Gln503X) results in a premature termination codon in the last exon, which is not expected to result in nonsense mediated decay (NMD), but is predicted to cause a truncation of the encoded protein, removing 31 amino acids. Truncations downstream of this position have been reported in affected individuals (HGMD), and been classified as pathogenic by our laboratory, and others in ClinVar. The variant allele was found at a frequency of 4e-06 in 251464 control chromosomes (gnomAD). The variant, c.1507C>T, has been reported in the literature in at least one apparently homozygous individual affected with Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome) of intermediate severity (Villani_1999). At least one publication reported greatly decreased enzyme activity, together with high levels of ARSB mRNA in patient derived fibroblast, indicating the lack of NMD (Bartolomeo_2012). The following publications have been ascertained in the context of this evaluation (PMID: 22971959, 26287674, 30118150, 10036316). Two other submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV000677494 SCV003525923 pathogenic Mucopolysaccharidosis type 6 2023-07-16 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Gln503*) in the ARSB gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 31 amino acid(s) of the ARSB protein. This variant is present in population databases (rs771113472, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with mucopolysaccharidosis type VI (PMID: 10036316). ClinVar contains an entry for this variant (Variation ID: 559719). This variant disrupts a region of the ARSB protein in which other variant(s) (p.Tyr513*) have been determined to be pathogenic (PMID: 10923267, 26909334). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing.
Baylor Genetics RCV000677494 SCV005055464 pathogenic Mucopolysaccharidosis type 6 2024-03-14 criteria provided, single submitter clinical testing

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