ClinVar Miner

Submissions for variant NM_000046.5(ARSB):c.247G>T (p.Asp83Tyr)

gnomAD frequency: 0.00001  dbSNP: rs1247117898
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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 RCV000677525 SCV000803036 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 RCV002298733 SCV002598636 uncertain significance not specified 2022-09-01 criteria provided, single submitter clinical testing Variant summary: ARSB c.247G>T (p.Asp83Tyr) 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 176126 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.247G>T has been reported in the literature as a presumed compound heterozygous genotype in at-least one individual affected with Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome) (example, Karageorgos_2007, cited in Tomanin_2018). These data do not allow any conclusion about variant significance. 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 uncertain significance citing an overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics RCV000677525 SCV002780468 uncertain significance Mucopolysaccharidosis type 6 2021-12-28 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000677525 SCV004293563 likely pathogenic Mucopolysaccharidosis type 6 2023-08-21 criteria provided, single submitter clinical testing This variant is not present in population databases (gnomAD no frequency). 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. 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. ClinVar contains an entry for this variant (Variation ID: 559749). This missense change has been observed in individual(s) with mucopolysaccharidosis type VI (PMID: 17458871). This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 83 of the ARSB protein (p.Asp83Tyr).

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