Submissions for variant NM_000046.5(ARSB):c.245T>G (p.Leu82Arg)

dbSNP: rs749465732

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Medical Molecular Genetics Department, National Research Center	RCV000656128	SCV000609482	pathogenic	Mucopolysaccharidosis type 6	2015-12-01	criteria provided, single submitter	research
SIB Swiss Institute of Bioinformatics	RCV000656128	SCV000787487	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: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect (PMID:18406185). PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:19259130).
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV000656128	SCV000803033	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 frequence in ExAC (PM2)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000656128	SCV001579936	pathogenic	Mucopolysaccharidosis type 6	2023-10-23	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 82 of the ARSB protein (p.Leu82Arg). This variant is present in population databases (no rsID available, gnomAD 0.001%). This missense change has been observed in individual(s) with mucopolysaccharidosis type VI (PMID: 17643332, 19259130). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 445290). 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. Experimental studies have shown that this missense change affects ARSB function (PMID: 18406185). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000656128	SCV004209903	pathogenic	Mucopolysaccharidosis type 6	2023-03-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000656128	SCV005395382	likely pathogenic	Mucopolysaccharidosis type 6	2024-09-19	criteria provided, single submitter	clinical testing	Variant summary: ARSB c.245T>G (p.Leu82Arg) 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 5.7e-06 in 176368 control chromosomes (gnomAD). c.245T>G has been reported in the literature in homozygous and compound heterozygous individuals affected with Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome) and this variant co-segregated with the disease (Garrido_2007, DiNatale_2008, Zanetti_2009). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 17672828, 17643332, 18406185, 30118150, 19259130). ClinVar contains an entry for this variant (Variation ID: 445290). Based on the evidence outlined above, the variant was classified as likely pathogenic.