ClinVar Miner

Submissions for variant NM_000046.5(ARSB):c.1534_1556del (p.Val512fs)

dbSNP: rs1310996698
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000677496 SCV001623154 pathogenic Mucopolysaccharidosis type 6 2021-05-13 criteria provided, single submitter clinical testing Variant summary: ARSB c.1534_1556del23 (p.Val512ProfsX3) 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. The variant allele was found at a frequency of 4e-06 in 251598 control chromosomes (gnomAD and publication data). c.1534_1556del23 has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome), including two homozygotes (Petry_2003, Petry_2005, Karageorgos_2007, Giraldo_2015). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
Mendelics RCV000677496 SCV002518521 pathogenic Mucopolysaccharidosis type 6 2022-05-04 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000677496 SCV003455707 pathogenic Mucopolysaccharidosis type 6 2023-03-13 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Val512Profs*3) in the ARSB gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 22 amino acid(s) of the ARSB protein. This variant is present in population databases (no rsID available, gnomAD 0.0009%). ClinVar contains an entry for this variant (Variation ID: 559721). This premature translational stop signal has been observed in individual(s) with mucopolysaccharidosis type VI (PMID: 17458871). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the ARSB protein in which other variant(s) (p.Thr526Metfs*48) have been determined to be pathogenic (PMID: 8116615, 24677745). 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 RCV000677496 SCV004209147 pathogenic Mucopolysaccharidosis type 6 2023-09-05 criteria provided, single submitter clinical testing
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova RCV000677496 SCV000803006 uncertain significance Mucopolysaccharidosis type 6 2018-01-01 flagged submission curation Absent from GnomAD (PM2

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