ClinVar Miner

Submissions for variant NM_000046.5(ARSB):c.629A>G (p.Tyr210Cys) (rs118203943)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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 2020-10-08 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 210 of the ARSB protein (p.Tyr210Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs118203943, ExAC 0.07%). This variant has been observed in several individuals and families affected with ARSB-related conditions (PMID: 8651289, 21514195, 24221504, 23557332, 17458871). ClinVar contains an entry for this variant (Variation ID: 885). Experimental studies have shown that this missense change has a deleterious effect on protein function (PMID: 8651289, 11939792, 23557332). For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000078003 SCV001248199 pathogenic not provided 2017-04-01 criteria provided, single submitter clinical testing
GeneDx RCV000078003 SCV001764303 pathogenic not provided 2019-03-04 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, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 8651289, 24221504, 21514195, 31589614, 23557332, 17458871, 30118150, 28552677, 18486607, 24389823, 22133300, 22441840, 14974081, 21917494, 15324318, 21791832, 24373060, 23657977)
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

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