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

gnomAD frequency: 0.00001  dbSNP: rs727503809

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000664046	SCV001586723	pathogenic	Mucopolysaccharidosis type 6	2023-10-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 315 of the ARSB protein (p.Arg315Gln). This variant is present in population databases (rs727503809, gnomAD 0.002%). This missense change 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 being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 166694). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ARSB function (PMID: 17161971). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000664046	SCV002813905	pathogenic	Mucopolysaccharidosis type 6	2022-02-10	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003415996	SCV004117993	pathogenic	ARSB-related disorder	2023-05-31	criteria provided, single submitter	clinical testing	The ARSB c.944G>A variant is predicted to result in the amino acid substitution p.Arg315Gln. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with mucopolysaccharidosis VI (see for example, Villani et al. 1999. PubMed ID: 10036316; Petry et al. 2005. PubMed ID: 16435196; Honjo et al. 2020. PubMed ID: 32075597; Andrade et al. 2022. PubMed ID: 35078524). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-78181605-C-T). This variant is interpreted as pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV000664046	SCV004171273	pathogenic	Mucopolysaccharidosis type 6		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000664046	SCV004210025	pathogenic	Mucopolysaccharidosis type 6	2022-09-01	criteria provided, single submitter	clinical testing