ClinVar Miner

Submissions for variant NM_000202.8(IDS):c.998C>T (p.Ser333Leu)

dbSNP: rs104894853
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000790725 SCV000232028 pathogenic not provided 2013-08-29 criteria provided, single submitter clinical testing
IIFP, CONICET-UNLP RCV000011233 SCV000262529 pathogenic Mucopolysaccharidosis, MPS-II 2010-04-16 criteria provided, single submitter research
Invitae RCV000011233 SCV001207067 pathogenic Mucopolysaccharidosis, MPS-II 2023-12-29 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 333 of the IDS protein (p.Ser333Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with mucopolysaccharidosis type II (MPS II) (PMID: 1639384, 28543354, 30639582; Invitae). ClinVar contains an entry for this variant (Variation ID: 10487). 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 IDS protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects IDS function (PMID: 17091340, 28543354). For these reasons, this variant has been classified as Pathogenic.
Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences RCV000011233 SCV001480194 pathogenic Mucopolysaccharidosis, MPS-II criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000011233 SCV002014474 pathogenic Mucopolysaccharidosis, MPS-II 2021-09-05 criteria provided, single submitter clinical testing
GeneDx RCV000790725 SCV002578620 pathogenic not provided 2022-10-05 criteria provided, single submitter clinical testing Published functional studies with S333L transfected into CHO, HEK293T, and COS-7 cells indicate a severe impairment of protein function (Sukegawa-Hayasaka et al., 2006; Vollebregt et al., 2017; Lin et al., 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16495038, 9921913, 9660053, 27246110, 1639384, 27695081, 30548430, 30639582, 9950361, 27896113, 27883178, 8830188, 28543354, 9875019, 21291454, 21829674, 33676511, 31877959, 34258227, 35144014, 17091340, 24125893)
Neuberg Centre For Genomic Medicine, NCGM RCV000011233 SCV005042552 pathogenic Mucopolysaccharidosis, MPS-II criteria provided, single submitter clinical testing The missense variant c.998C>Tp.Ser333Leu in IDS gene has been reported previously in hemizygous state in most of the individuals with mucopolysaccharidosis type II. Experimental studies have shown that this missense change affects IDS function Sukegawa-Hayasaka K, et al., 2006, Vollebregt AAM, et al., 2017. The variant is novel not in any individuals in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic multiple submissions.The amino acid Serine at position 333 is changed to a Leucine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by SIFT. The amino acid change p.Ser333Leu in IDS is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000011233 SCV000031460 pathogenic Mucopolysaccharidosis, MPS-II 1992-07-01 no assertion criteria provided literature only
GeneReviews RCV000011233 SCV000999926 not provided Mucopolysaccharidosis, MPS-II no assertion provided literature only
Pediatrics, All India Institute of Medical Sciences, New Delhi RCV000011233 SCV001573787 affects Mucopolysaccharidosis, MPS-II 2014-04-07 no assertion criteria provided research The change c.998C>T (p.S333L) was found to be a missense variant, where the hydroxyl-containing polar neutral amino acid Serine at 333 position was substituted by aliphatic nonpolar neutral amino acid Leucine. It was detected in a hemizygous state in one case with severe phenotype from Haryana, India.
Developmental and Behavioral Pediatrics, First Affiliated Hospital of Jilin University RCV000011233 SCV002575080 pathogenic Mucopolysaccharidosis, MPS-II no assertion criteria provided provider interpretation

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