rs199422231

Variant names:

• chrX-149482997-G-A
• rs199422231
• NM_000202.8:c.1402C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_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. R468G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: IDS NM_000202.8 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13 O:2
• Conservation: PhyloP100: 1.83

Genes affected

IDS (HGNC:5389): (iduronate 2-sulfatase) This gene encodes a member of the sulfatase family of proteins. The encoded preproprotein is proteolytically processed to generate two polypeptide chains. This enzyme is involved in the lysosomal degradation of heparan sulfate and dermatan sulfate. Mutations in this gene are associated with the X-linked lysosomal storage disease mucopolysaccharidosis type II, also known as Hunter syndrome. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. [provided by RefSeq, Jan 2016]

ENSG00000241489 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a chain Iduronate 2-sulfatase 14 kDa chain (size 94) in uniprot entity IDS_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_000202.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967
• PP5: Variant X-149482997-G-A is Pathogenic according to our data. Variant chrX-149482997-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10497.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-149482997-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDS	NM_000202.8	c.1402C>T	p.Arg468Trp	missense_variant	Exon 9 of 9	ENST00000340855.11	NP_000193.1
IDS	NM_001166550.4	c.1132C>T	p.Arg378Trp	missense_variant	Exon 9 of 9		NP_001160022.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDS	ENST00000340855.11	c.1402C>T	p.Arg468Trp	missense_variant	Exon 9 of 9	1	NM_000202.8	ENSP00000339801.6
ENSG00000241489	ENST00000651111.1	c.769C>T	p.Arg257Trp	missense_variant	Exon 14 of 14			ENSP00000498395.1
ENSG00000241489	ENST00000422081.6	c.769C>T	p.Arg257Trp	missense_variant	Exon 9 of 9	2		ENSP00000477056.1
ENSG00000241489	ENST00000441880.1	n.*93C>T		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-II Pathogenic:10 Other:2

Jan 25, 2024

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PP3+PM5+PS3_Moderate+PS4 -

Jun 10, 2014

IIFP, CONICET-UNLP

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jun 26, 2017

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 05, 2014

Division of Medical Genetics, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi

Significance: Affects

Review Status: no assertion criteria provided

Collection Method: 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. -

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Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 07, 2024

Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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) -

Sep 05, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 26, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

May 09, 2022

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jul 12, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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). Experimental studies have shown that this missense change affects IDS function (PMID: 1284597, 15614569). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Jul 28, 2014

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 05, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Expression studies found that this variant is associated with 0%-0.6% of wild-type IDS activity levels (PMID: 15614569); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 1284597, 27351199, 34813777, 35144014, 12048688, 29966168, 28077157, 15614569, 33676511, 30639582) -

Mucopolysaccharidosis, type II, mild form Pathogenic:1

Dec 01, 1992

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.67	D
BayesDel_noAF	Pathogenic	0.72
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D;.
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	3.6	H;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-7.7	D;.
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.57
MutPred		0.85		Loss of disorder (P = 0.0043);.;
MVP		1.0
MPC		0.80
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.94
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199422231; hg19: chrX-148564528;