rs398123249

Variant names:

• chrX-149503468-G-A
• rs398123249
• NM_000202.8:c.262C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000202.8(IDS):​c.262C>T​(p.Arg88Cys) variant causes a missense change. 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R88H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: IDS NM_000202.8 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 3.74
• Publications: 12 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 18 ACMG points.

• PM1: In a hotspot region, there are 30 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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-149503467-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 950955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996
• PP5: Variant X-149503468-G-A is Pathogenic according to our data. Variant chrX-149503468-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 92618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDS	NM_000202.8	c.262C>T	p.Arg88Cys	missense_variant	Exon 3 of 9	ENST00000340855.11	NP_000193.1
IDS	NM_006123.5	c.262C>T	p.Arg88Cys	missense_variant	Exon 3 of 8		NP_006114.1
IDS	NR_104128.2	n.431C>T		non_coding_transcript_exon_variant	Exon 3 of 9
IDS	NM_001166550.4	c.15-23C>T		intron_variant	Intron 2 of 8		NP_001160022.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDS	ENST00000340855.11	c.262C>T	p.Arg88Cys	missense_variant	Exon 3 of 9	1	NM_000202.8	ENSP00000339801.6
ENSG00000241489	ENST00000651111.1	c.-215-2431C>T		intron_variant	Intron 8 of 13			ENSP00000498395.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-II Pathogenic:8

Sep 01, 2022

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

The hemizygous status for variant c.262C>T(p.Arg88Cys) in exon 3 of IDS gene. The variant has not been repoted in the 1000 genome gnomAD databases. The in silico prediction is damaging by DANN, LRT, SIFT and MutationTaster. -

Jul 26, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine with cysteine at codon 88 of the IDS protein (p.Arg88Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in several individuals affected with mucopolysaccharidosis type II (PMID: 7814022, 8940265 , 9950361 , 15614569, 17063374, 22990955, 24125893, 26762690). ClinVar contains an entry for this variant (Variation ID: 92618). Experimental studies have shown that this missense change affects IDS post-translational modification and results in a protein with an almost undetectable enzymatic activity (PMID: 15614569, 22990955). For these reasons, this variant has been classified as Pathogenic. A different missense substitution at this codon (p.Arg88His) has been determined to be pathogenic (PMID: 9921913, 9660053, 10215411, 10838181, 24515576). This suggests that the arginine residue is critical for IDS protein function and that other missense substitutions at this position may also be pathogenic. -

Jun 30, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 23, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: IDS c.262C>T (p.Arg88Cys) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 114316 control chromosomes (gnomAD). c.262C>T has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type II (Hunter Syndrome) (e.g. Parkinson_2004, Chang_2005, Froissart_2007, Charoenwattanasatien_2012, Dvorakova_2017). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrated the variant confers very little residual IDS activity (Chang_2005, Charoenwattanasatien_2012). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

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), Located in a mutational hot spot and/or critical functional domain (PM1_Moderate), 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_Strong) -

not provided Pathogenic:2

Jun 08, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate reduced IDS enzyme activity (Chang et al., 2005; Charoenwattanasatien et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 7814022, 22990955, 15614569, 35144014, 32036093, 27695081, 33676511, 30639582, 34813777, 26762690, 31877959) -

Jan 09, 2013

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.69	D
BayesDel_noAF	Pathogenic	0.76
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.;D
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	1.0	D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	5.0	H;H;.
PhyloP100		3.7
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-7.4	D;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.89
MutPred		0.98		Loss of disorder (P = 0.0525);Loss of disorder (P = 0.0525);Loss of disorder (P = 0.0525);
MVP		1.0
MPC		2.6
ClinPred		1.0	D
GERP RS		2.3
Varity_R		0.99
gMVP		1.0
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs398123249; hg19: chrX-148584998;