ClinVar Miner

Submissions for variant NM_000046.5(ARSB):c.215T>G (p.Leu72Arg) (rs397514441)

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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 RCV000677516 SCV000803026 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); Absent from GnomAD (PM2); Reputable source identifies as pathogenic (PP5)
Invitae RCV000677516 SCV000955328 pathogenic Mucopolysaccharidosis type 6 2019-07-18 criteria provided, single submitter clinical testing This sequence change replaces leucine with arginine at codon 72 of the ARSB protein (p.Leu72Arg). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and arginine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in individuals with mucopolysaccharidosis type VI (PMID: 16435196, 17458871, 25190157, Invitae). 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: 559740). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000677516 SCV001370604 pathogenic Mucopolysaccharidosis type 6 2020-05-07 criteria provided, single submitter clinical testing Variant summary: ARSB c.215T>G (p.Leu72Arg) 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 allele was found at a frequency of 5.5e-06 in 182450 control chromosomes. c.215T>G has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome) with early onset and classical, rapidly progressing disease phenotype in the homozygotes (Petry_2005, Karageorgos_2007). These data indicate that the variant is very likely to be associated with disease. One of these publications also reported very low or undetectable ASB protein levels and undetectable enzymatic activities in skin fibroblasts derived from homozygous patients (Karageorgos_2007). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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