Submissions for variant NM_000202.8(IDS):c.1402C>T (p.Arg468Trp)

dbSNP: rs199422231

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723439	SCV000232921	pathogenic	not provided	2014-07-28	criteria provided, single submitter	clinical testing
IIFP, CONICET-UNLP	RCV000180471	SCV000262540	pathogenic	Mucopolysaccharidosis, MPS-II	2014-06-10	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000180471	SCV000695962	pathogenic	Mucopolysaccharidosis, MPS-II	2017-06-26	criteria provided, single submitter	clinical testing	Variant summary: The IDS c.1402C>T (p.Arg468Trp) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 159432 control chromosomes. This variant has been reported in multiple affected individuals mostly presented with severe form of the disease. Functional studies showed variant with <5% of WTs enzyme activity. Variant affecting the same codon R468Q has also been reported in multiple affected males presenting with Mucopolysaccharidosis type II (Hunter syndrome), suggesting the functional importance of this residue. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000180471	SCV001376052	pathogenic	Mucopolysaccharidosis, MPS-II	2023-07-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 468 of the IDS protein (p.Arg468Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with mucopolysaccharidosis type II (PMID: 1284597, 15614569, 28077157, 30639582). ClinVar contains an entry for this variant (Variation ID: 10497). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on IDS protein function. Experimental studies have shown that this missense change affects IDS function (PMID: 1284597, 15614569). For these reasons, this variant has been classified as Pathogenic.
Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences	RCV000180471	SCV001480197	pathogenic	Mucopolysaccharidosis, MPS-II		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000180471	SCV002014468	pathogenic	Mucopolysaccharidosis, MPS-II	2021-09-05	criteria provided, single submitter	clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000180471	SCV002507185	likely pathogenic	Mucopolysaccharidosis, MPS-II	2022-05-09	criteria provided, single submitter	clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000180471	SCV004232630	pathogenic	Mucopolysaccharidosis, MPS-II	2024-01-25	criteria provided, single submitter	clinical testing	A hemizygous missense variation in exon 9 of the IDS gene that results in the amino acid substitution of Tryptophan for Arginine at codon 468 was detected. The observed variant c.1402C>T (p.Arg468Trp) has not been reported in the 1000 genomes and gnomAD databases. The in silico prediction of the variant is damaging by PolyPhen-2 (HumDiv), SIFT, FATHMM, DANN, MetaLR and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a pathogenic.
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV000180471	SCV005089553	pathogenic	Mucopolysaccharidosis, MPS-II	2024-06-07	criteria provided, single submitter	literature only	In vitro or in vivo functional studies supportive of a damaging effect (PS3_Strong), Prevalence of the variant significantly increased in affected individuals compared with controls (PS4_Strong), Absent from controls (or at low frequency) in gnomAD database (PM2_Moderate), Missense variant in a gene with a low rate of benign missense variation (PP2_Supporting), Multiple lines of computational evidence support a deleterious effect (PP3_Supporting), Patient’s phenotype or family history highly specific for the disease (PP4_Moderate)
OMIM	RCV000011243	SCV000031470	pathogenic	Mucopolysaccharidosis, type II, mild form	1992-12-01	no assertion criteria provided	literature only
GeneReviews	RCV000180471	SCV000999928	not provided	Mucopolysaccharidosis, MPS-II		no assertion provided	literature only
Counsyl	RCV000180471	SCV001132228	pathogenic	Mucopolysaccharidosis, MPS-II	2017-06-26	no assertion criteria provided	clinical testing
Pediatrics, All India Institute of Medical Sciences, New Delhi	RCV000180471	SCV001573783	affects	Mucopolysaccharidosis, MPS-II	2014-04-05	no assertion criteria provided	research	The change c.1402C>T (p.R468W) was found to be a missense variant, where the basic polar positive amino acid Arginine at 468 position is substituted by aromatic nonpolar neutral amino acid Tryptophan. It was detected in a hemizygous state in three patients from two families. All three with attenuated phenotypes from UP (2 sibs) Jharkhand (single patient) India.