rs199422231
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000202.8(IDS):c.1402C>T(p.Arg468Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R468L) has been classified as Pathogenic.
Frequency
Consequence
NM_000202.8 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IDS | NM_000202.8 | c.1402C>T | p.Arg468Trp | missense_variant | 9/9 | ENST00000340855.11 | |
IDS | NM_001166550.4 | c.1132C>T | p.Arg378Trp | missense_variant | 9/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IDS | ENST00000340855.11 | c.1402C>T | p.Arg468Trp | missense_variant | 9/9 | 1 | NM_000202.8 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD4 exome Cov.: 30
GnomAD4 genome ? Cov.: 23
ClinVar
Submissions by phenotype
Mucopolysaccharidosis, MPS-II Pathogenic:8Other:2
Pathogenic, criteria provided, single submitter | clinical testing | Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 26, 2017 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics | Jan 25, 2024 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 12, 2023 | 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. - |
Pathogenic, criteria provided, single submitter | research | IIFP, CONICET-UNLP | Jun 10, 2014 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Jun 26, 2017 | - - |
Affects, no assertion criteria provided | research | Pediatrics, All India Institute of Medical Sciences, New Delhi | Apr 05, 2014 | 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. - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | May 09, 2022 | - - |
Mucopolysaccharidosis, type II, mild form Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 1992 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 28, 2014 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at