NM_000202.8:c.257C>T

Variant names:

• chrX-149503473-G-A
• rs1557340280
• NM_000202.8:c.257C>T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP3 PP5_Very_Strong

The NM_000202.8(IDS):​c.257C>T​(p.Pro86Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P86R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: IDS NM_000202.8 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.42
• Publications: 11 publications found

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]

IDS Gene-Disease associations (from GenCC):

• mucopolysaccharidosis type 2

  Inheritance: XL, AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, PanelApp Australia, Myriad Women’s Health
• mucopolysaccharidosis type 2, attenuated form

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• mucopolysaccharidosis type 2, severe form

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000241489 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PM1: In a hotspot region, there are 29 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain 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 chrX-149503473-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 996919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-149503473-G-A is Pathogenic according to our data. Variant chrX-149503473-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 527322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000202.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDS	NM_000202.8	MANE Select	c.257C>T	p.Pro86Leu	missense	Exon 3 of 9	NP_000193.1
	IDS	NM_006123.5		c.257C>T	p.Pro86Leu	missense	Exon 3 of 8	NP_006114.1
	IDS	NR_104128.2		n.426C>T		non_coding_transcript_exon	Exon 3 of 9

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDS	ENST00000340855.11	TSL:1 MANE Select	c.257C>T	p.Pro86Leu	missense	Exon 3 of 9	ENSP00000339801.6
	IDS	ENST00000370441.8	TSL:1	c.257C>T	p.Pro86Leu	missense	Exon 3 of 8	ENSP00000359470.4
	IDS	ENST00000466323.5	TSL:1	n.257C>T		non_coding_transcript_exon	Exon 3 of 9	ENSP00000418264.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-II Pathogenic:4

Jun 29, 2022

Revvity Omics, Revvity

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), Cosegregation with disease in multiple affected family members (PP1_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)

Jun 15, 2022

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) performed at Invitae indicates that this missense variant is expected to disrupt IDS protein function. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change affects IDS function (PMID: 9573369, 26407519). ClinVar contains an entry for this variant (Variation ID: 527322). This missense change has been observed in individual(s) with mucopolysaccharidosis (MPS) type II (PMID: 7728156, 9573369, 10215411, 17063374, 22976768, 24515576, 28077157). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 86 of the IDS protein (p.Pro86Leu).

Jun 20, 2025

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 variant in exon 3 of the IDS gene that results in the amino acid substitution of Leucine for Proline at codon 86 was detected. The observed variant c.257C>T (p.Pro86Leu) has not been reported in the 1000 genomes and gnomAD databases. The in silico prediction of the variant is deleterious by Mutation Taster, SIFT, FATHMM and DANN. In summary, the variant meets our criteria to be classified as pathogenic.

Inborn genetic diseases Pathogenic:1

Jun 05, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P86L pathogenic mutation (also known as c.257C>T), located in coding exon 3 of the IDS gene, results from a C to T substitution at nucleotide position 257. The proline at codon 86 is replaced by leucine, an amino acid with a few similar properties. This mutation has been detected in several individuals with Mucopolysaccharidosis type II (MPS II; also called Hunter syndrome) (Popowska E, et al. Hum. Mutat. 1995;5(1):97-100; Vafiadaki E, et al. Arch. Dis. Child. 1998 79(3):237-41; Isogai K, et al. J. Inherit. Metab. Dis. 1998;21(1):60-70; Lampe C et al. JIMD Rep, 2014 Mar;14:99-113; Kosuga M et al. Mol. Genet. Metab., 2016 07;118:190-7), and occurred de novo in at least one individual (Chiong MA et al. Orphanet J Rare Dis, 2017 01;12:7). In addition, several functional studies have shown that this mutation disrupts splicing, resulting in a truncated mRNA product which causes a decrease in IDS enzymatic activity and lysosomal formation (Isogai K, et al. J. Inherit. Metab. Dis. 1998;21(1):60-70; Sukegawa-Hayasaka K, et al. J. Inherit. Metab. Dis. 2006 Dec; 29(6):755-61; Matos L et al. Biochim. Biophys. Acta, 2015 Dec;1852:2712-21; Millat G et al. Biochim. Biophys. Acta, 1998 Mar;1406:214-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

not provided Pathogenic:1

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

IDS: PM1, PM2, PM5, PM6, PS4:Moderate, PP3, PS3:Supporting

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.82
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	5.0	H
PhyloP100		9.4
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-9.2	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.98		Loss of loop (P = 0.0804)
MVP		1.0
MPC		2.2
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.98
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.62		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.62		Position offset: -28

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

Other links and lift over

dbSNP: rs1557340280; hg19: chrX-148585003;