rs113993948

Variant names:

• chrX-149486983-G-A
• rs113993948
• NM_000202.8:c.1122C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-149486983-G-A
• chrX-149486983-G-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_000202.8(IDS):​c.1122C>T​(p.Gly374Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G374G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: IDS NM_000202.8 synonymous
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11 O:2
• Conservation: PhyloP100: -0.137

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

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-149486983-G-A is Pathogenic according to our data. Variant chrX-149486983-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10491.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-149486983-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.1122C>T	p.Gly374Gly	synonymous_variant	Exon 8 of 9	ENST00000340855.11	NP_000193.1
IDS	NM_001166550.4	c.852C>T	p.Gly284Gly	synonymous_variant	Exon 8 of 9		NP_001160022.1
IDS	NM_006123.5	c.*305C>T		downstream_gene_variant			NP_006114.1
IDS	NR_104128.2	n.*148C>T		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDS	ENST00000340855.11	c.1122C>T	p.Gly374Gly	synonymous_variant	Exon 8 of 9	1	NM_000202.8	ENSP00000339801.6
ENSG00000241489	ENST00000651111.1	c.489C>T	p.Gly163Gly	synonymous_variant	Exon 13 of 14			ENSP00000498395.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-II Pathogenic:10 Other:2

Apr 13, 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.1122C>T is a known cryptic splice generator variant. This mutation is due to the substitution of C to T at nucleotide position c.11122 in the exon 8 of IDS gene. In the present study, it was detected in a hemizygous state in one of the patient with severe phenotype from Delhi, India. Uttarilli et al., 2016 described its presence in six MPS II patients of which four with severe phenotype and two with an attenuated phenotype. -

Dec 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects codon 374 of the IDS mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the IDS protein. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 20 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with mucopolysaccharidosis type II (PMID: 8940265, 16133661, 17063374, 21829674, 22976768, 27146977). This variant is also known as c.1246C>T. ClinVar contains an entry for this variant (Variation ID: 10491). Studies have shown that this variant results in the activation of a cryptic splice site in exon 8 (PMID: 8940265, 26407519, 26693516). For these reasons, this variant has been classified as Pathogenic. -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Sep 23, 2023

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A hemizygous variant in exon 8 of the IDS gene that results in the amino acid substitution of Glycine for Glycine at codon 374 was detected. The observed variant c.1122C>T has not been reported in the 1000 genomes and gnomAD databases. The in-silico prediction of the variant is damaging by Splice AI tool. In summary, the variant meets our criteria to be classified as likely pathogenic. -

-

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 13, 2007

IIFP, CONICET-UNLP

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Sep 05, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 07, 2023

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The IDS c.1122C>T p.(Gly374=) synonymous variant is one of the most commonly reported disease-causing variants in IDS. This variant has been identified in individuals with mucopolysaccharidosis type II (MPSII) and was reported in a de novo state in at least one of these individuals (PMID: 8940265; 20301451; 27146977; 30639582; 31877959; 33676511; 34006472). This variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Functional studies show that the c.1122C>T variant results in activation of a cryptic splice site within exon 8 of the IDS gene leading to a deletion of 20 amino acids (PMID: 8940265; 26407519; 26693516). Based on the available evidence, the c.1122C>T p.(Gly374=) variant is classified as pathogenic for mucopolysaccharidosis type II. -

Jul 01, 1992

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 31, 2019

Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jun 24, 2024

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.1122C>T alters a non-conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a 5' donor site. One predict the variant strengthens a 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (e.g. Rathman_1996, Matos_2015) . The variant was absent in 183469 control chromosomes. c.1122C>T has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type II (Hunter Syndrome) (e.g. Rathman_1996, Gort_1998, Uttarilli_2016). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 9452044, 26407519, 8940265, 27146977). ClinVar contains an entry for this variant (Variation ID: 10491). 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_Moderate), 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), Patient’s phenotype or family history highly specific for the disease (PP4_Strong) -

not provided Pathogenic:1

Sep 07, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate that this variant creates a new splice donor site resulting in skipping of the last 60 nucleotides of exon 8 (Matos et al. 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 8940265, 8281149, 21829674, 16133661, 26407519, 1639384, 17063374, 9921913, 16495038, 30639582, 21291454, 27146977, 11462244, 33676511, 35144014, 34006472, 31877959, 26693516) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	19
DANN	Benign	0.82
Mutation Taster		=100/0	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
SpliceAI score (max)		0.94		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.94		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs113993948; hg19: chrX-148568514; COSMIC: COSV61711594; COSMIC: COSV61711594;