ClinVar Miner

Submissions for variant NM_000046.5(ARSB):c.215T>A (p.Leu72Gln)

dbSNP: rs397514441
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224599 SCV000280768 pathogenic not provided 2015-06-12 criteria provided, single submitter clinical testing
Laboratory of Diagnosis and Therapy of Lysosomal Disorders,University of Padova RCV000677514 SCV000803024 uncertain significance Mucopolysaccharidosis type 6 2018-01-01 criteria provided, single submitter curation Absent from GnomAD (PM2)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000779750 SCV000916525 uncertain significance not specified 2018-04-19 criteria provided, single submitter clinical testing Variant summary: ARSB c.215T>A (p.Leu72Gln) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 30582 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.215T>A, has been reported in the literature in one individual affected with Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome)(Isbrandt_1995), together with the likely pathogenic (in our internal database) variant c.219_230delinsG (p.Asp73fsX50) on the same allele and c.743delC (p.Pro248Leufs*5) on the other allele, suggesting a potential benign effect. The same publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect. However, 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 pathogenic. In addition, multiple reports in HGMD related to other variants affecting this codon suggest this might be a hotspot. Based on the evidence outlined above, the variant was classified as uncertain significance.
OMIM RCV000000931 SCV000021081 pathogenic Mucopolysaccharidosis, type vi, severe 1996-01-01 no assertion criteria provided literature only

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