ClinVar Miner

Submissions for variant NM_000046.5(ARSB):c.944G>A (p.Arg315Gln) (rs727503809)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000152796 SCV000202186 pathogenic not provided 2014-02-14 criteria provided, single submitter clinical testing
SIB Swiss Institute of Bioinformatics RCV000664046 SCV000787460 likely pathogenic Mucopolysaccharidosis type 6 2018-04-16 criteria provided, single submitter curation This variant is interpreted as a Likely Pathogenic, for Mucopolysaccharidosis type VI, Autosomal Recessive inheritance. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:16435196). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => PS4 downgraded in strength to Moderate (PMID:16435196) (PMID:19259130) (PMID:14974081).
Laboratory of Diagnosis and Therapy of Lysosomal Disorders,University of Padova RCV000664046 SCV000803129 likely pathogenic Mucopolysaccharidosis type 6 2018-01-01 criteria provided, single submitter curation In vitro functional studies supportive of a damaging effect on the gene product (low to no ARSB activity in homozygotes; PS3); Very low frequency in ExAC (PM2); Reputable source identifies as pathogenic (PP5)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000664046 SCV001572522 pathogenic Mucopolysaccharidosis type 6 2021-04-14 criteria provided, single submitter clinical testing Variant summary: ARSB c.944G>A (p.Arg315Gln) results in a conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.9e-06 in 251738 control chromosomes (gnomAD and publication data). c.944G>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome) (Villani_1999, Karageorgos_2004, Karageorgos_2006, Garrido_2007, Zanetti_2009, Honjo_2020). These data indicate that the variant is very likely to be associated with disease. Functional studies report experimental evidence evaluating an impact on protein function and the variant effect results in decreasing ARSB protein and activity (Karageorgos_2004, Karageorgos_2006). Two ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000664046 SCV001586723 pathogenic Mucopolysaccharidosis type 6 2020-08-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 315 of the ARSB protein (p.Arg315Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs727503809, ExAC 0.003%). This variant has been observed in individual(s) with mucopolysaccharidosis type VI (PMID: 10036316, 17161971, 17458871, 26937411). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 166694). This variant has been reported to affect ARSB protein function (PMID: 17161971). For these reasons, this variant has been classified as Pathogenic.

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