ClinVar Genomic variation as it relates to human health
NM_000203.5(IDUA):c.265C>T (p.Arg89Trp)
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_000203.5(IDUA):c.265C>T (p.Arg89Trp)
Variation ID: 580286 Accession: VCV000580286.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4p16.3 4: 987915 (GRCh38) [ NCBI UCSC ] 4: 981703 (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 Oct 10, 2018 Feb 14, 2024 Sep 30, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000203.5:c.265C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000194.2:p.Arg89Trp missense NM_022042.4:c.*918G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
3 prime UTR NM_134425.4:c.576+3213G>A intron variant NM_213613.4:c.*918G>A 3 prime UTR NR_110313.1:n.353C>T non-coding transcript variant NC_000004.12:g.987915C>T NC_000004.11:g.981703C>T NG_008103.1:g.5919C>T NG_033042.1:g.10522G>A LRG_1277:g.5919C>T LRG_1277t1:c.265C>T LRG_1277p1:p.Arg89Trp - Protein change
- R89W
- Other names
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- Canonical SPDI
- NC_000004.12:987914:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
- Links
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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IDUA | - | - |
GRCh38 GRCh37 |
1386 | 2132 | |
SLC26A1 | - | - |
GRCh38 GRCh37 |
3 | 748 |
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 (3) |
criteria provided, multiple submitters, no conflicts
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Sep 30, 2023 | RCV000703774.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 2, 2021 | RCV001784344.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Aug 18, 2021 | RCV002485752.1 |
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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Pathogenic
(Apr 30, 2019)
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criteria provided, single submitter
Method: clinical testing
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Mucopolysaccharidosis type 1
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001363955.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: IDUA c.265C>T (p.Arg89Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: IDUA c.265C>T (p.Arg89Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.4e-05 in 221338 control chromosomes (gnomAD and publication data) and has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type 1 (e.g. Bunge_1995, Bertola_2011, Ahmed_2014, Pineda 2014) and most of the cases presented with an attenuated- (Scheie syndrome) or intermediate phenotype (Hurler-Scheie syndrome). These data indicate that the variant is very likely to be associated with disease. Functional characterization demonstrated the variant protein was present in a similar- or increased amount in cell lines from patients compared to controls, but had a severely reduced enzymatic activity in both patient derived cell lines and transfected Chinese hamster ovary cells (Bunge_1998, Hein_2003); since some residual activity was preserved, it is consistent with the less severe clinical presentation of the reported patients (Hein_2003). One submitter has provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Aug 18, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hurler syndrome
Mucopolysaccharidosis, MPS-I-H/S Mucopolysaccharidosis, MPS-I-S
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002792110.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Dec 02, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002023090.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Sep 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Mucopolysaccharidosis type 1
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000832691.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg89 amino acid residue in IDUA. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg89 amino acid residue in IDUA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8664897, 12559846, 14559116). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects IDUA function (PMID: 14559116). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt IDUA protein function. ClinVar contains an entry for this variant (Variation ID: 580286). This missense change has been observed in individuals with MPS I (PMID: 7550242, 14559116, 21394825, 22306676, 24368159, 27896125). This variant is present in population databases (rs754966840, gnomAD 0.007%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 89 of the IDUA protein (p.Arg89Trp). (less)
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Pathogenic
(Nov 14, 2020)
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no assertion criteria provided
Method: clinical testing
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Mucopolysaccharidosis type I
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002083092.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Genotypic and bioinformatic evaluation of the alpha-l-iduronidase gene and protein in patients with mucopolysaccharidosis type I from Colombia, Ecuador and Peru. | Pineda T | Molecular genetics and metabolism reports | 2014 | PMID: 27896125 |
Neurocognitive and neuropsychiatric phenotypes associated with the mutation L238Q of the α-L-iduronidase gene in Hurler-Scheie syndrome. | Ahmed A | Molecular genetics and metabolism | 2014 | PMID: 24368159 |
Analysis of cDNA molecules is not suitable for the molecular diagnosis of Mucopolysaccharidosis type I. | Almeida AC | Diagnostic molecular pathology : the American journal of surgical pathology, part B | 2012 | PMID: 22306676 |
IDUA mutational profiling of a cohort of 102 European patients with mucopolysaccharidosis type I: identification and characterization of 35 novel α-L-iduronidase (IDUA) alleles. | Bertola F | Human mutation | 2011 | PMID: 21394825 |
The alpha-L-iduronidase mutations R89Q and R89W result in an attenuated mucopolysaccharidosis type I clinical presentation. | Hein LK | Biochimica et biophysica acta | 2003 | PMID: 14559116 |
Identification and characterization of 13 new mutations in mucopolysaccharidosis type I patients. | Matte U | Molecular genetics and metabolism | 2003 | PMID: 12559846 |
Genotype-phenotype correlations in mucopolysaccharidosis type I using enzyme kinetics, immunoquantification and in vitro turnover studies. | Bunge S | Biochimica et biophysica acta | 1998 | PMID: 9748610 |
Mucopolysaccharidosis type I: identification of common mutations that cause Hurler and Scheie syndromes in Japanese populations. | Yamagishi A | Human mutation | 1996 | PMID: 8664897 |
Mucopolysaccharidosis type I: identification of 13 novel mutations of the alpha-L-iduronidase gene. | Bunge S | Human mutation | 1995 | PMID: 7550242 |
Text-mined citations for rs754966840 ...
HelpRecord last updated Mar 17, 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.