ClinVar Genomic variation as it relates to human health
NM_000203.5(IDUA):c.1598C>G (p.Pro533Arg)
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.1598C>G (p.Pro533Arg)
Variation ID: 11910 Accession: VCV000011910.41
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4p16.3 4: 1003418 (GRCh38) [ NCBI UCSC ] 4: 997206 (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 Apr 18, 2015 May 1, 2024 Jan 30, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000203.5:c.1598C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000194.2:p.Pro533Arg missense NM_001363576.1:c.1202C>G NP_001350505.1:p.Pro401Arg missense NR_110313.1:n.1686C>G non-coding transcript variant NC_000004.12:g.1003418C>G NC_000004.11:g.997206C>G NG_008103.1:g.21422C>G LRG_1277:g.21422C>G LRG_1277t1:c.1598C>G LRG_1277p1:p.Pro533Arg P35475:p.Pro533Arg - Protein change
- P533R, P401R
- Other names
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- Canonical SPDI
- NC_000004.12:1003417:C:G
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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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00006
Exome Aggregation Consortium (ExAC) 0.00000
The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00005
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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 (5) |
criteria provided, multiple submitters, no conflicts
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Jan 30, 2024 | RCV000208595.23 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Apr 27, 2023 | RCV000486848.20 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 31, 2022 | RCV001267070.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 16, 2022 | RCV000763533.11 | |
Pathogenic (3) |
criteria provided, single submitter
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Jul 3, 2019 | RCV000012685.26 |
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
Help
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
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 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 27, 2023)
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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: SCV002023123.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 30, 2024)
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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: SCV000933163.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 533 of the IDUA protein (p.Pro533Arg). … (more)
This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 533 of the IDUA protein (p.Pro533Arg). This variant is present in population databases (rs121965021, gnomAD 0.02%). This missense change has been observed in individuals with mucopolysaccharidosis (PMID: 1301941, 10911525, 16435195, 21521498, 23786846, 24368159). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11910). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects IDUA function (PMID: 24036510). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 31, 2022)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV001445251.4
First in ClinVar: Nov 21, 2020 Last updated: May 01, 2024 |
Comment:
The c.1598C>G (p.P533R) alteration is located in coding exon 11 of the IDUA gene. This alteration results from a C to G substitution at nucleotide … (more)
The c.1598C>G (p.P533R) alteration is located in coding exon 11 of the IDUA gene. This alteration results from a C to G substitution at nucleotide position 1598, causing the proline (P) at amino acid position 533 to be replaced by an arginine (R). Based on data from gnomAD, the G allele has an overall frequency of 0.01% (8/157288) total alleles studied. The highest observed frequency was 0.02% (1/4962) of Other alleles. This alteration has been reported in the homozygous or compound heterozygous state in individuals with mucopolysaccharidosis type I (Scott, 1992; Laradi, 2005; Fahiminiya, 2014; Ghosh, 2017; Clarke, 2019). Patients have presented with both the attenuated and severe phenotypes (Scott, 1992; Laradi, 2005; Clarke, 2019). This variant occurs with high frequency in the Moroccan, Sicilian, and Brazilian populations (reviewed in Matte, 2003). This amino acid position is highly conserved in available vertebrate species. Functional analysis has demonstrated that the p.P533R variant significantly decreases protein activity as compared to wild type protein. Fibroblast cells lines from a patient with this alteration and a second nonsense alteration had 0.5% of normal activity, while two homozygous patients had leukocyte protein activity at 1.2% of normal (Scott, 1992; Laradi, 2005). When expressed in CHO-K1 cells, this variant produced a small amount of protein that did not appear to undergo normal processing and had 0.04% of normal protein activity (Matte, 2003). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Jan 14, 2020)
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criteria provided, single submitter
Method: curation
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Mucopolysaccharidosis type 1
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001422984.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 05, 2022 |
Comment:
The p.Pro533Arg variant in IDUA has been reported in at least 15 individuals with mucopolysaccharidosis (MPS), segregated with disease in 6 affected relatives from 3 … (more)
The p.Pro533Arg variant in IDUA has been reported in at least 15 individuals with mucopolysaccharidosis (MPS), segregated with disease in 6 affected relatives from 3 families (PMID: 19748810, 27196898, 28752568) and has been Identified in 0.012% (3/24988) of Latino chromosomes and 0.006% (4/62590) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121965021). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (VariationID: 11910) as pathogenic by GeneDx, EGL Genetic Diagnostics, Fulgent Genetics, OMIM, Integrated Genetics, and GeneReviews. In vitro functional studies provide some evidence that the p.Pro533Arg variant may slightly impact protein function (PMID: 24036510). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Pro533Arg variant is located in a region of IDUA that is essential to protein folding and stability, suggesting that this variant is in a functional domain and supports pathogenicity (PMID: 24036510). The phenotype of individuals homozygous and compound heterozygous for this variant is highly specific for MPS1 based on alpha-L-iduronidase levels being <1% of normal consistent with disease (PMID: 27196898). Additionally, the presence of this variant in at least 18 affected homozygotes and in combination with reported pathogenic variants in 2 individuals with MPS increases the likelihood that the p.Pro533Arg variant is pathogenic (VariationID: 11908, 280976; PMID: 19748810, 27196898, 28752568). In summary, this variant meets criteria to be classified as pathogenic for MPS1 in an autosomal recessive manner based on the presence of the variant in affected homozygotes and compound heterozygotes, co-segregation with disease, and the deleterious effect of the variant on protein folding and function. ACMG/AMP Criteria applied: PM3_strong, PP1_moderate, PM1, PM2_supporting, PP3, PP4, PS3_supporting (Richards 2015). (less)
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Pathogenic
(May 08, 2017)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000700446.2
First in ClinVar: Apr 02, 2018 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
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Pathogenic
(Sep 28, 2016)
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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: SCV000568512.4
First in ClinVar: Apr 27, 2017 Last updated: Dec 15, 2018 |
Comment:
The P533R variant in the IDUA gene has been reported previously in individuals with MPS I in the homozygous state or in the heterozygous state … (more)
The P533R variant in the IDUA gene has been reported previously in individuals with MPS I in the homozygous state or in the heterozygous state with a presumed second IDUA variant (Alif et al., 1999; Laradi et al., 2005; Fahiminiya et al., 2014). The P533R variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P533R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Functional studies of P533R indicate that this variant leads to a 50% reduction in the enzymatic rate of IDUA and confers lower thermodynamic stability compared to wild type protein (Bie et al., 2013). A missense variant in the same residue, P533L, has been previously identified in patients with MPS I in the homozygous state and in the heterozygous state with a second IDUA variant (Voskoboeva et al., 1998; Atceken et al., 2016). Therefore, we interpret P533R as a pathogenic variant. (less)
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Pathogenic
(Dec 15, 2017)
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criteria provided, single submitter
Method: clinical testing
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Mucopolysaccharidosis type I
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000919533.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: The IDUA c.1598C>G (p.Pro533Arg) variant involves the alteration of a conserved nucleotide. 3/3 in silico tools predict a damaging outcome for this variant … (more)
Variant summary: The IDUA c.1598C>G (p.Pro533Arg) variant involves the alteration of a conserved nucleotide. 3/3 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 8/152678 control chromosomes at a frequency of 0.0000524, which does not exceed the estimated maximal expected allele frequency of a pathogenic IDUA variant (0.0026926). The variant was reported in numerous affected individuals in the literature in both the homozygous and compound heterozygous state. Homozygous patients have been reported to have undetectable IDUA activity (Chkioua_2011). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
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Pathogenic
(Jul 03, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hurler syndrome
Affected status: yes
Allele origin:
unknown
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Baylor Genetics
Accession: SCV001520420.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
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Pathogenic
(Mar 16, 2022)
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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: SCV000894346.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
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Pathogenic
(Jan 01, 1999)
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no assertion criteria provided
Method: literature only
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HURLER SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000032920.3
First in ClinVar: Apr 04, 2013 Last updated: Apr 18, 2015 |
Comment on evidence:
By chemical cleavage analysis followed by direct PCR sequencing, Scott et al. (1992) detected an alteration of the proline at position 533 to an arginine … (more)
By chemical cleavage analysis followed by direct PCR sequencing, Scott et al. (1992) detected an alteration of the proline at position 533 to an arginine in the alpha-L-iduronidase protein. Using allele-specific oligonucleotides to screen for the mutation in a group of 73 MPS I (607014) patients, they found that the P533R mutation accounted for 3% of alleles. Homozygotes for the P533R mutation showed an extremely severe clinical phenotype; compound heterozygotes showed a wide range of clinical phenotypes. Scott et al. (1992) found that 3 mutations, W402X, Q70X, and P533R, were responsible for 53% of MPS I alleles, which together defined 28% of MPS I genotypes. Using fluorescence-assisted mismatch analysis (FAMA) and cycle sequencing of the PCR products, Alif et al. (1999) screened for mutations in the IDUA gene in a group of 13 Moroccan patients with MPS I and their families, including 3 sibs and twin sibs. The P553R mutation, which is rare in Europeans, was identified in 92% of mutant alleles (24 of 26). This was said to be the highest frequency of this mutation detected in patients with Hurler syndrome. None of the patients carried the W402X (252800.0001) or the Q70X (252800.0002) allele, the most common MPS I mutations in Europeans. (less)
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Pathogenic
(Jul 28, 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: SCV002075377.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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Pathogenic
(Dec 09, 2016)
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no assertion criteria provided
Method: clinical testing
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Hurler syndrome
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV001132229.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001952782.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001969420.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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Mucopolysaccharidosis type 1
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000264386.3
First in ClinVar: Mar 05, 2016 Last updated: Oct 01, 2022 |
Comment:
Common pathogenic variant in Italy
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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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Mucopolysaccharidosis Type I. | Adam MP | - | 2024 | PMID: 20301341 |
Genotype-phenotype relationships in mucopolysaccharidosis type I (MPS I): Insights from the International MPS I Registry. | Clarke LA | Clinical genetics | 2019 | PMID: 31194252 |
IDUA mutational profile and genotype-phenotype relationships in UK patients with Mucopolysaccharidosis Type I. | Ghosh A | Human mutation | 2017 | PMID: 28752568 |
Clinical and Molecular Characterization of Patients with Mucopolysaccharidosis Type I in an Algerian Series. | Tebani A | International journal of molecular sciences | 2016 | PMID: 27196898 |
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 |
Whole exome sequencing unravels disease-causing genes in consanguineous families in Qatar. | Fahiminiya S | Clinical genetics | 2014 | PMID: 24102521 |
Insights into mucopolysaccharidosis I from the structure and action of α-L-iduronidase. | Bie H | Nature chemical biology | 2013 | PMID: 24036510 |
Residual α-L-iduronidase activity in fibroblasts of mild to severe Mucopolysaccharidosis type I patients. | Oussoren E | Molecular genetics and metabolism | 2013 | PMID: 23786846 |
Hurler disease (mucopolysaccharidosis type IH): clinical features and consanguinity in Tunisian population. | Chkioua L | Diagnostic pathology | 2011 | PMID: 22074387 |
Mucopolysaccharidosis type I: molecular characteristics of two novel alpha-L-iduronidase mutations in Tunisian patients. | Chkioua L | Diagnostic pathology | 2011 | PMID: 21639919 |
Molecular analysis of mucopolysaccharidosis type I in Tunisia: identification of novel mutation and eight Novel polymorphisms. | Chkioua L | Diagnostic pathology | 2011 | PMID: 21521498 |
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 |
Treatment reduces or stabilizes brain imaging abnormalities in patients with MPS I and II. | Wang RY | Molecular genetics and metabolism | 2009 | PMID: 19748810 |
Mucopolysaccharidosis I: Alpha-L-Iduronidase mutations in three Tunisian families. | Laradi S | Journal of inherited metabolic disease | 2005 | PMID: 16435195 |
Identification and characterization of 13 new mutations in mucopolysaccharidosis type I patients. | Matte U | Molecular genetics and metabolism | 2003 | PMID: 12559846 |
Mutational analysis of 85 mucopolysaccharidosis type I families: frequency of known mutations, identification of 17 novel mutations and in vitro expression of missense mutations. | Beesley CE | Human genetics | 2001 | PMID: 11735025 |
[Mucopolysaccharidosis type I in Morocco: clinical features and genetic profile]. | Alif N | Archives de pediatrie : organe officiel de la Societe francaise de pediatrie | 2000 | PMID: 10911525 |
Mucopolysaccharidosis type I: characterization of a common mutation that causes Hurler syndrome in Moroccan subjects. | Alif N | Annals of human genetics | 1999 | PMID: 10738517 |
alpha-L-iduronidase mutations (Q70X and P533R) associate with a severe Hurler phenotype. | Scott HS | Human mutation | 1992 | PMID: 1301941 |
A common mutation for mucopolysaccharidosis type I associated with a severe Hurler syndrome phenotype. | Scott HS | Human mutation | 1992 | PMID: 1301196 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=IDUA | - | - | - | - |
http://www.ncbi.nlm.nih.gov/sites/GeneTests/review/gene/IDUA | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/9e19dffd-6728-44eb-85a4-85aebc9bdf86 | - | - | - | - |
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Text-mined citations for rs121965021 ...
HelpRecord last updated May 08, 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.