Submissions for variant NM_000046.5(ARSB):c.629A>G (p.Tyr210Cys)

gnomAD frequency: 0.00017  dbSNP: rs118203943

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000078003	SCV000109841	pathogenic	not provided	2013-07-25	criteria provided, single submitter	clinical testing
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV000000933	SCV000803096	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); Prevalence of the variant in affected is increased compared with controls (PS4); Reputable source identifies as pathogenic (PP5)
Fulgent Genetics, Fulgent Genetics	RCV000000933	SCV000894363	pathogenic	Mucopolysaccharidosis type 6	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779747	SCV000916522	pathogenic	Metachromatic leukodystrophy	2017-11-02	criteria provided, single submitter	clinical testing	Variant summary: The ARSB c.629A>G (p.Tyr210Cys) variant located in the Sulfatase, N-termail (via InterPro) involves the alteration of a conserved nucleotide and 5/5 in silico tools predict a damaging outcome for this variant. A functional study, Brands_2013, supports these predictions by observing the variant to cause a significant decrease in ARSB activity in comparison to wild type. This variant was found in 75/277016 control chromosomes (gnomAD), predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.000569 (72/126548), which does not exceed the estimated maximal expected allele frequency of a pathogenic ARSB variant (0.0022361). Multiple publications have cited the variant homozygously and in compound heterozygosity in affected individuals and indicated the variant to be one of the of most common mutations (Karageorgos_2007). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae	RCV000000933	SCV000957251	pathogenic	Mucopolysaccharidosis type 6	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 210 of the ARSB protein (p.Tyr210Cys). This variant is present in population databases (rs118203943, gnomAD 0.06%). This missense change has been observed in individuals with ARSB-related conditions (PMID: 8651289, 17458871, 21514195, 23557332, 24221504). ClinVar contains an entry for this variant (Variation ID: 885). 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: 8651289, 11939792, 23557332). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000078003	SCV001248199	pathogenic	not provided	2017-04-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000078003	SCV001764303	pathogenic	not provided	2022-05-02	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that expression of Y210C mutant cell lines results in approximately 2% residual arylsulfatase activity, supporting a damaging effect (Litjens et al., 1996; Brands et al., 2013).; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21917494, 15324318, 28552677, 21791832, 23657977, 24373060, 24221504, 23557332, 8651289, 14974081, 22441840, 22133300, 24389823, 18486607, 17458871, 30118150, 33209960, 31589614, 21514195)
Revvity Omics, Revvity	RCV000000933	SCV002018841	pathogenic	Mucopolysaccharidosis type 6	2021-02-22	criteria provided, single submitter	clinical testing
3billion	RCV000000933	SCV003842048	pathogenic	Mucopolysaccharidosis type 6	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.027%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 11939792, 23557332, 8651289). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97; 3Cnet: 1.00). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 4 similarly affected unrelated individuals (PMID: 17458871, 21514195, 23557332, 24221504, 8651289). A different missense change at the same codon (p.Tyr210His) has been reported to be associated with ARSB related disorder (ClinVar ID: VCV001469785). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Baylor Genetics	RCV000000933	SCV004206738	pathogenic	Mucopolysaccharidosis type 6	2023-10-05	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003904792	SCV004719154	pathogenic	ARSB-related condition	2024-01-22	criteria provided, single submitter	clinical testing	The ARSB c.629A>G variant is predicted to result in the amino acid substitution p.Tyr210Cys. This variant has been reported to be causative for mucopolysaccharidosis VI syndrome (see for example Litjens et al 1996. PubMed ID: 8651289; Brands et al. 2013. PubMed ID: 23557332; Jurecka. 2014. PubMed ID: 24221504). This variant is reported in 0.056% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.
OMIM	RCV000000933	SCV000021083	pathogenic	Mucopolysaccharidosis type 6	1996-06-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000000933	SCV001457627	pathogenic	Mucopolysaccharidosis type 6	2020-09-16	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000078003	SCV001739615	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000078003	SCV001954793	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000078003	SCV001974238	pathogenic	not provided		no assertion criteria provided	clinical testing