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

dbSNP: rs104894853

Total submissions: 11

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