rs113993948

chrX-149486983-G-AchrX-149486983-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_000202.8(IDS):c.1122C>T(p.Gly374=) 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:9 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]

ACMG classification

Verdict is Pathogenic. Variant got 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/exons	MANE	UniProt
IDS	NM_000202.8	c.1122C>T	p.Gly374=	synonymous_variant	8/9	ENST00000340855.11
IDS	NM_001166550.4	c.852C>T	p.Gly284=	synonymous_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IDS	ENST00000340855.11	c.1122C>T	p.Gly374=	synonymous_variant	8/9	1	NM_000202.8	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-II Pathogenic:8 Other:2

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Likely 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	Invitae	Sep 27, 2022	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. For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant results in the activation of a cryptic splice site in exon 8 (PMID: 8940265, 26407519, 26693516). ClinVar contains an entry for this variant (Variation ID: 10491). This variant is also known as c.1246C>T. This variant has been observed in individuals with mucopolysaccharidosis type II (PMID: 8940265, 16133661, 17063374, 21829674, 22976768, 27146977). This variant is not present in population databases (gnomAD no frequency). -
Pathogenic, no assertion criteria provided	research	Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital	May 31, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Sep 23, 2023	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 1992	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 07, 2023	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. -
Affects, no assertion criteria provided	research	Pediatrics, All India Institute of Medical Sciences, New Delhi	Apr 13, 2014	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. -
Pathogenic, criteria provided, single submitter	research	IIFP, CONICET-UNLP	Nov 13, 2007	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 07, 2022

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

Splicing

Name	Calibrated prediction	Score	Prediction
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;