rs113993948
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_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 (★★).
Frequency
Genomes: not found (cov: 22)
Consequence
IDS
NM_000202.8 synonymous
NM_000202.8 synonymous
Scores
2
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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 | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| IDS | NM_000202.8 | c.1122C>T | p.Gly374= | synonymous_variant | 8/9 | ENST00000340855.11 | NP_000193.1 | |
| IDS | NM_001166550.4 | c.852C>T | p.Gly284= | synonymous_variant | 8/9 | NP_001160022.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| IDS | ENST00000340855.11 | c.1122C>T | p.Gly374= | synonymous_variant | 8/9 | 1 | NM_000202.8 | ENSP00000339801 | P1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
22
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
GnomAD4 genome
Cov.:
22
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:11Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Mucopolysaccharidosis, MPS-II Pathogenic:10Other:2
| 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 | Labcorp Genetics (formerly Invitae), Labcorp | 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 | literature only | OMIM | Jul 01, 1992 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
| Pathogenic, criteria provided, single submitter | research | IIFP, CONICET-UNLP | Nov 13, 2007 | - - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| 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, no assertion criteria provided | research | Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital | May 31, 2019 | - - |
| Pathogenic, criteria provided, single submitter | literature only | Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova | Jun 07, 2024 | 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) - |
| 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. - |
| 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, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 24, 2024 | 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. - |
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:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at