ClinVar Miner

Submissions for variant NM_000046.5(ARSB):c.438G>A (p.Trp146Ter) (rs757061042)

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Total submissions: 3
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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 RCV000677566 SCV000803079 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 RCV000677566 SCV001442541 pathogenic Mucopolysaccharidosis type 6 2020-10-12 criteria provided, single submitter clinical testing Variant summary: ARSB c.438G>A (p.Trp146X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251470 control chromosomes. c.438G>A has been reported in the literature in individuals affected with Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome) (example, Karageorgos_2007, Thumler_2012, Tomanin_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000677566 SCV001579934 pathogenic Mucopolysaccharidosis type 6 2020-10-26 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp146*) in the ARSB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ARSB are known to be pathogenic (PMID: 17458871, 22133300). This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with mucopolysaccharidosis type VI (PMID: 17458871). ClinVar contains an entry for this variant (Variation ID: 559787). For these reasons, this variant has been classified as Pathogenic.

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