ClinVar Genomic variation as it relates to human health
NM_000202.8(IDS):c.1122C>T (p.Gly374=)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000202.8(IDS):c.1122C>T (p.Gly374=)
Variation ID: 10491 Accession: VCV000010491.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq28 X: 149486983 (GRCh38) [ NCBI UCSC ] X: 148568514 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Feb 20, 2014 Feb 28, 2024 Sep 23, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000202.8:c.1122C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000193.1:p.Gly374= synonymous NM_000202.4:c.1122C>T NM_001166550.4:c.852C>T NP_001160022.1:p.Gly284= synonymous NC_000023.11:g.149486983G>A NC_000023.10:g.148568514G>A NG_011900.3:g.23352C>T NG_042264.1:g.338G>A - Protein change
- Other names
- p.Gly374=
- Canonical SPDI
- NC_000023.11:149486982:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- effect on RNA splicing Variation Ontology [VariO:0362]
- The 1-nt silent variant creates a cryptic donor splice site, which results in the splicing-out of the distal 60-nt of exon 8. [curated by NCBI staff]
- cryptic splice donor activation Variation Ontology [VariO:0374]
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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IDS | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
416 | 1072 | |
LOC106050102 | - | - | - | GRCh38 | - | 504 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (10) |
criteria provided, multiple submitters, no conflicts
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Sep 23, 2023 | RCV000011237.24 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 7, 2022 | RCV002284352.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Mucopolysaccharidosis, MPS-II
(X-linked recessive inheritance)
Affected status: yes
Allele origin:
germline
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Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences
Accession: SCV001480480.1
First in ClinVar: Feb 20, 2021 Last updated: Feb 20, 2021 |
Number of individuals with the variant: 3
Clinical Features:
Motor delay (present) , Low maternal circulating estriol concentration (present) , Coarse facial features (present) , Depressed nasal bridge (present) , Short stature (present) , … (more)
Motor delay (present) , Low maternal circulating estriol concentration (present) , Coarse facial features (present) , Depressed nasal bridge (present) , Short stature (present) , Macrocephaly (present) , Sleep apnea (present) , Flexion contracture (present) , Hearing impairment (present) , Abnormal heart valve morphology (present) , Hurler syndrome (present) , Inguinal hernia (present) , Hepatosplenomegaly (present) (less)
Age: 6-11 years
Sex: male
Ethnicity/Population group: Indian
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Pathogenic
(Sep 07, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002574624.2
First in ClinVar: Sep 24, 2022 Last updated: Mar 04, 2023 |
Comment:
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 … (more)
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) (less)
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Pathogenic
(Nov 13, 2007)
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criteria provided, single submitter
Method: research
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Mucopolysaccharidosis, MPS-II
(X-linked inheritance)
Affected status: yes
Allele origin:
maternal
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IIFP, CONICET-UNLP
Accession: SCV000262535.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Number of individuals with the variant: 4
Sex: male
Geographic origin: Argentina
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Likely pathogenic
(Sep 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Mucopolysaccharidosis, MPS-II
(X-linked recessive inheritance)
Affected status: yes
Allele origin:
germline
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV004040634.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Joint contracture (present) , Coarse facial features (present)
Age: 10-19 years
Sex: male
Method: DNA extracted from blood was used to perform targeted gene capture using a custom smMIP panel. The libraries were sequenced to mean >100-300X coverage on the Illumina MiSeq sequencing platform. The sequences obtained are aligned to the human reference genome (GRCh37) using the BWA program and analyzed using Picard and GATK version 4.1.2 to identify variants relevant to the clinical indication.
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Pathogenic
(Sep 07, 2023)
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criteria provided, single submitter
Method: clinical testing
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Mucopolysaccharidosis, MPS-II
Affected status: unknown
Allele origin:
unknown
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Illumina Laboratory Services, Illumina
Accession: SCV004101336.1
First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Sep 27, 2022)
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criteria provided, single submitter
Method: clinical testing
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Mucopolysaccharidosis, MPS-II
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000628120.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
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 … (more)
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). (less)
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Pathogenic
(Sep 05, 2021)
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criteria provided, single submitter
Method: clinical testing
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Mucopolysaccharidosis, MPS-II
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002014472.1
First in ClinVar: Nov 13, 2021 Last updated: Nov 13, 2021 |
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Pathogenic
(Jul 01, 1992)
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no assertion criteria provided
Method: literature only
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MUCOPOLYSACCHARIDOSIS, TYPE II
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000031464.2
First in ClinVar: Apr 04, 2013 Last updated: Feb 20, 2014 |
Comment on evidence:
In their patient 3 with Hunter syndrome (309900), Flomen et al. (1992) found in genomic DNA a C-to-T transition at nucleotide 1246 of the IDS … (more)
In their patient 3 with Hunter syndrome (309900), Flomen et al. (1992) found in genomic DNA a C-to-T transition at nucleotide 1246 of the IDS gene, which produced no change in the sense of the codon, i.e., was silent, but created a cryptic donor splice site leading to partial loss of an exon. Sixty basepairs were lost from the cDNA, from G1244 to G1305. (less)
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Pathogenic
(May 31, 2019)
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no assertion criteria provided
Method: research
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Mucopolysaccharidosis, MPS-II
Affected status: yes
Allele origin:
de novo
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Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital
Accession: SCV001482353.1
First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
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Affects
(Apr 13, 2014)
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no assertion criteria provided
Method: research
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Mucopolysaccharidosis, MPS-II
(X-linked recessive inheritance)
Affected status: yes
Allele origin:
germline
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Pediatrics, All India Institute of Medical Sciences, New Delhi
Accession: SCV001573802.1
First in ClinVar: May 10, 2021 Last updated: May 10, 2021 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Coarse facial features (present) , Arthropathy (present) , Hepatosplenomegaly (present) , Hernia (present) , Intellectual disability (present) , Abnormal echocardiogram (present)
Age: 20-29 years
Sex: male
Ethnicity/Population group: INDIAN
Geographic origin: New Delhi, India
Comment on evidence:
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 … (more)
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. (less)
Method: Sanger sequencing was performed on ABI 3130 genetic analyser (Applied Biosystem, USA) capillary electrophoresis. Data was analysed by ABI sequence analysis (SeqScape version 2.5) software as well as manually by using software: Chromaspro (Version-1.7.5, Technilysium Pvt. Ltd, Australia) and FinchTV (Version 1.4.0, Geospiza, Perkinelmer, USA).
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not provided
(-)
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no classification provided
Method: literature only
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Mucopolysaccharidosis, MPS-II
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000999929.2
First in ClinVar: Dec 17, 2019 Last updated: Oct 01, 2022 |
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
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A brief description of the result of this method for this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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cryptic splice donor activation
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Pediatrics, All India Institute of Medical Sciences, New Delhi
Accession: SCV001573802.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Mucopolysaccharidosis Type II. | Adam MP | - | 2024 | PMID: 20301451 |
Identification and characterization of 20 novel pathogenic variants in 60 unrelated Indian patients with mucopolysaccharidoses type I and type II. | Uttarilli A | Clinical genetics | 2016 | PMID: 27146977 |
Data in support of a functional analysis of splicing mutations in the IDS gene and the use of antisense oligonucleotides to exploit an alternative therapy for MPS II. | Matos L | Data in brief | 2015 | PMID: 26693516 |
Functional analysis of splicing mutations in the IDS gene and the use of antisense oligonucleotides to exploit an alternative therapy for MPS II. | Matos L | Biochimica et biophysica acta | 2015 | PMID: 26407519 |
Identification of 17 novel mutations in 40 Argentinean unrelated families with mucopolysaccharidosis type II (Hunter syndrome). | Amartino H | Molecular genetics and metabolism reports | 2014 | DOI: 10.1016/j.ymgmr.2014.08.006 |
Molecular characterization of 355 mucopolysaccharidosis patients reveals 104 novel mutations. | Pollard LM | Journal of inherited metabolic disease | 2013 | PMID: 22976768 |
Analysis of the IDS gene in 38 patients with Hunter syndrome: the c.879G>A (p.Gln293Gln) synonymous variation in a female create exonic splicing. | Zhang H | PloS one | 2011 | PMID: 21829674 |
Molecular characterization of Portuguese patients with mucopolysaccharidosis type II shows evidence that the IDS gene is prone to splicing mutations. | Alves S | Journal of inherited metabolic disease | 2006 | PMID: 17063374 |
Mutational and structural analysis of Japanese patients with mucopolysaccharidosis type II. | Kato T | Journal of human genetics | 2005 | PMID: 16133661 |
Mucopolysaccharidosis type II (Hunter syndrome): mutation "hot spots" in the iduronate-2-sulfatase gene. | Rathmann M | American journal of human genetics | 1996 | PMID: 8940265 |
Detection of point mutations and a gross deletion in six Hunter syndrome patients. | Flomen RH | Genomics | 1992 | PMID: 1639384 |
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Text-mined citations for rs113993948 ...
HelpRecord last updated Feb 28, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.