ClinVar Miner

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

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Total submissions: 6
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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
Fulgent Genetics,Fulgent Genetics RCV000000933 SCV000894363 pathogenic Mucopolysaccharidosis type VI 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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 VI 2018-11-28 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.
Laboratory of Diagnosis and Therapy of Lysosomal Disorders,University of Padova RCV000000933 SCV000803096 pathogenic Mucopolysaccharidosis type VI 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)
OMIM RCV000000933 SCV000021083 pathogenic Mucopolysaccharidosis type VI 1996-06-01 no assertion criteria provided literature only

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