ClinVar Genomic variation as it relates to human health
NM_000203.5(IDUA):c.208C>T (p.Gln70Ter)
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.208C>T (p.Gln70Ter)
Variation ID: 11909 Accession: VCV000011909.49
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4p16.3 4: 987858 (GRCh38) [ NCBI UCSC ] 4: 981646 (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 12, 2024 Apr 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000203.5:c.208C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000194.2:p.Gln70Ter nonsense NM_022042.4:c.*975G>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+3270G>A intron variant NM_213613.4:c.*975G>A 3 prime UTR NR_110313.1:n.296C>T non-coding transcript variant NC_000004.12:g.987858C>T NC_000004.11:g.981646C>T NG_008103.1:g.5862C>T NG_033042.1:g.10579G>A LRG_1277:g.5862C>T LRG_1277t1:c.208C>T LRG_1277p1:p.Gln70Ter - Protein change
- Q70*
- Other names
- -
- Canonical SPDI
- NC_000004.12:987857: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
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00037
The Genome Aggregation Database (gnomAD), exomes 0.00047
The Genome Aggregation Database (gnomAD) 0.00063
Exome Aggregation Consortium (ExAC) 0.00065
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
Help
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 | 2133 | |
SLC26A1 | - | - |
GRCh38 GRCh37 |
3 | 749 |
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 (4) |
criteria provided, multiple submitters, no conflicts
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Nov 12, 2019 | RCV000012684.40 | |
Pathogenic (2) |
criteria provided, single submitter
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Dec 3, 2018 | RCV000185562.12 | |
Pathogenic (2) |
criteria provided, single submitter
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Jun 12, 2019 | RCV000185563.11 | |
Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Jan 25, 2024 | RCV000276574.31 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 8, 2022 | RCV000763532.11 | |
Pathogenic (10) |
criteria provided, multiple submitters, no conflicts
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Apr 1, 2024 | RCV000790700.27 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV001526587.10 | |
IDUA-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Aug 29, 2022 | RCV003390671.4 |
Pathogenic (1) |
criteria provided, single submitter
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Aug 6, 2023 | RCV003488336.1 |
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
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
(Dec 24, 2014)
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criteria provided, single submitter
Method: clinical testing
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Mucopolysaccharidosis type 1
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Study: CSER-MedSeq
Accession: SCV000245622.1 First in ClinVar: Sep 14, 2015 Last updated: Sep 14, 2015 |
Comment:
The p.Gln70X variant in IDUA has been reported in several individuals with Mucopolysaccharidosis type I (MPSI) in a homozygous or compound heterozygous state with another … (more)
The p.Gln70X variant in IDUA has been reported in several individuals with Mucopolysaccharidosis type I (MPSI) in a homozygous or compound heterozygous state with another pathogenic variant, and is estimated to account for 10-15% of this disease in different European populations (Scott 1992, Clarke 1993, Gatti 1997, Gort 1997, Vazna 2009, Pollard 2013). The Gln70X variant led to reduced residual enzyme activity in functional studies (Oussoren 2013). This variant has also been identified in 0.3% (17/5282) of Finnish chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs121965020), and in 0.1% (10/8592) of European chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). This frequency is consistent with the estimated carrier frequency of MPSI (Moore 2008). This nonsense variant leads to a premature termination codon at position 70, which is predicted to lead to a truncated or absent protein. Loss of function of the IDUA gene is an established disease mechanism in individuals with MPSI. In summary, this variant meets our criteria to be classified as pathogenic for MPSI in an autosomal recessive manner (http://www.partners.org/personalizedmedicine/LMM). (less)
Number of individuals with the variant: 1
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Pathogenic
(Aug 04, 2016)
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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: SCV000695971.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Comment:
Variant summary: The IDUA c.208C>T (p.Gln70X) variant results in a premature termination codon 584 amino acids from the end of the protein, predicted to cause … (more)
Variant summary: The IDUA c.208C>T (p.Gln70X) variant results in a premature termination codon 584 amino acids from the end of the protein, predicted to cause a truncated or absent IDUA protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Trp402X). The residual activity of IDUA was measured in fibroblast cell lines from a patient homozygous for Gln70X, showing that activity was essentially no activity, indicating that this is a null allele. One in silico tool predicts a damaging outcome for this variant. This variant was found in 72/110336 control chromosomes at a frequency of 0.0006526, which does not exceed the estimated maximal expected allele frequency of a pathogenic IDUA variant (0.0026926). However, the variant has been cited in many Hurler Syndrome (MPS IH, severe presentation) patients in both homozygous and compound heterozygous states. 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
(Apr 27, 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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Illumina Laboratory Services, Illumina
Accession: SCV000451736.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The IDUA c.208C>T (p.Gln70Ter) variant is a stop gained variant that is well described in the literature as a common pathogenic variant for mucopolysaccharidosis type … (more)
The IDUA c.208C>T (p.Gln70Ter) variant is a stop gained variant that is well described in the literature as a common pathogenic variant for mucopolysaccharidosis type I, estimated to account for ten to thirty-five percent of disease alleles in different European populations. The variant is usually associated with a severe phenotype. In a sample of eight studies involving a total of 280 individuals, the p.Gln70Ter variant was found in 17 affected individuals in a homozygous state, 26 individuals in a compound heterozygous state, and in five individuals in a heterozygous state (Scott et al. 1992; Clarke et al. 1993; Bunge et al. 1994; Gort et al. 1998; Beesley et al. 2001; Vazna et al. 2009; Pollard et al. 2013; Oussoren et al. 2013). The variant was absent from 140 control alleles but is reported at a frequency of 0.00325 in the European (Finnish) population from the Exome Aggregation Consortium. Several studies reported that there was either no or very low residual enzyme activity in all individual samples (Scott et al. 1992; Vazna et al. 2009; Oussoren et al. 2013). Oussoren et al. (2013) demonstrated that individuals who were homozygous or compound heterozygous for the p.Gln70Ter variant showed residual IDUA activity of 0.1% and 0.2% of control activity, respectively. An immunochemical assay found no detectable protein in cell lines derived from individuals who were homozygous or compound heterozygous for the variant (Scott et al. 1992). Based on the collective evidence, the p.Gln70Ter variant is classified as pathogenic for mucopolysaccharidosis type I. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Aug 09, 2013)
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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: SCV000227059.5
First in ClinVar: Jun 28, 2015 Last updated: Jul 30, 2019 |
Number of individuals with the variant: 37
Sex: mixed
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Pathogenic
(Dec 03, 2018)
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criteria provided, single submitter
Method: research
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Mucopolysaccharidosis, MPS-I-H/S
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001164455.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
Comment:
The heterozygous p.Gln70Ter variant in IDUA was identified by our study in the compound heterozygous state, with another pathogenic variant, in one individual with Hurler-Scheie … (more)
The heterozygous p.Gln70Ter variant in IDUA was identified by our study in the compound heterozygous state, with another pathogenic variant, in one individual with Hurler-Scheie syndrome. The presence of this variant in combination with a likely pathogenic variant and in an individual with Hurler-Scheie syndrome increases the likelihood that the p.Gln70Ter variant is pathogenic. This variant has been identified in 0.05257% (142/270128) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121965020). 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 is a well-known pathogenic variant in Europeans with Hurler-Scheie syndrome that was reported in the homozygous and heterozygous state (32/200 alleles) of individuals with Hurler-Scheie syndrome from two cohorts (PMID: 22976768, 29393969, 11735025). This variant has also been reported pathogenic in ClinVar (Variation ID: 11909). This nonsense variant leads to a premature termination codon at position 70, which is predicted to lead to a truncated or absent protein. Loss of function of the IDUA gene is an established disease mechanism in autosomal recessive Hurler-Scheie syndrome, and this is a loss of function variant. In summary, this variant meets criteria to be classified as pathogenic for Hurler Scheie syndrome in an autosomal recessive manner based on the predicted impact of the variant and multiple occurrences in European individuals with Hurler Scheie syndrome. ACMG/AMP Criteria applied: PM2, PVS1, PM3 (Richards 2015). (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: research
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Mucopolysaccharidosis type 1
Affected status: no
Allele origin:
germline
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UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill
Study: NSIGHT-NC NEXUS
Accession: SCV001251495.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020
Comment:
carrier finding
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Comment:
The IDUA c.208C>T (p.Q70*) nonsense variant is predicted to result in an absent or aberrant protein. This variant has been reported in individuals with MPS … (more)
The IDUA c.208C>T (p.Q70*) nonsense variant is predicted to result in an absent or aberrant protein. This variant has been reported in individuals with MPS I (PMID: 1301941; 1505961; 8401515; 7951228; 9427149; 9787109; 10215409; 11735025; 19396826). (less)
Number of individuals with the variant: 1
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Pathogenic
(Oct 24, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hurler syndrome
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Genomic Medicine Lab, University of California San Francisco
Study: CSER-P3EGS
Accession: SCV001572976.1 First in ClinVar: May 10, 2021 Last updated: May 10, 2021 |
Sex: female
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Interstitial pneumonitis
Affected status: yes
Allele origin:
maternal
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV001737014.1
First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021
Comment:
Compound heterozygous (other variant: PED8814.12), both variants inherited from one parent
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Pathogenic
(Jan 13, 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: SCV001422679.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 05, 2022 |
Comment:
The p.Gln70Ter variant has been reported in at least 22 individuals with mucopolysaccharidosis (MPS) (PMID: 28752568) and has been identified in Identified in 0.194% (48/24766) … (more)
The p.Gln70Ter variant has been reported in at least 22 individuals with mucopolysaccharidosis (MPS) (PMID: 28752568) and has been identified in Identified in 0.194% (48/24766) of European (Finnish) chromosomes, 0.069% (85/122916) of European (non-Finnish) chromosomes, and 0.069% (4/14378) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP s121965020). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (VariationID: 11909) as pathogenic by 10 submitters. In vitro functional studies provide some evidence that the p.Gln70Ter variant may impact protein function (PMID: 11159948). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 70, which is predicted to lead to a truncated or absent protein. Loss of function of the IDUA gene is an established disease mechanism in autosomal recessive MPS. The presence of this variant in combination with a reported pathogenic variant and in 20 individuals with MPS increases the likelihood that the p.Gln70Ter variant is pathogenic (VariationID: 11908, 222996; PMID: 28752568). The phenotype of individuals compound heterozygous for this variant is highly specific for MPS based on enzyme activity being less than 1% of normal consistent with disease (PMID: 28752568). In summary, this variant meets criteria to be classified as pathogenic for MPS in an autosomal recessive manner based on the prediction that it will cause loss of function, the presence of the variant in combination with other pathogenic variants, and functional studies. ACMG/AMP Criteria applied: PVS1, PM3_very-strong, PS3, PP4 (Richards 2015). (less)
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Pathogenic
(Feb 13, 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: SCV002023095.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
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Pathogenic
(Apr 01, 2024)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004811019.2
First in ClinVar: Apr 15, 2024 Last updated: May 12, 2024 |
Comment:
IDUA: PM3:Very Strong, PVS1, PM2
Number of individuals with the variant: 3
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Pathogenic
(Nov 12, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hurler syndrome
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV001194218.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020 |
Comment:
NM_000203.3(IDUA):c.208C>T(Q70*) is classified as pathogenic in the context of mucopolysaccharidosis type I. Sources cited for classification include the following: PMID 21394825, 19396826, 10215409 and 23786846. … (more)
NM_000203.3(IDUA):c.208C>T(Q70*) is classified as pathogenic in the context of mucopolysaccharidosis type I. Sources cited for classification include the following: PMID 21394825, 19396826, 10215409 and 23786846. Classification of NM_000203.3(IDUA):c.208C>T(Q70*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. (less)
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Pathogenic
(Jun 12, 2019)
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criteria provided, single submitter
Method: clinical testing
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Mucopolysaccharidosis, MPS-I-S
Affected status: yes
Allele origin:
unknown
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Baylor Genetics
Accession: SCV001520422.1
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 06, 2020)
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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: SCV001168420.1
First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 21831683, 30737479, 29654546, 7951228, 8401515, 24368159, 25525159, 22976768, 24314423, 1301941, 31133280, 23786846, 31980526, 31589614) (less)
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Pathogenic
(Apr 08, 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: SCV000894344.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
|
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Pathogenic
(Aug 29, 2022)
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criteria provided, single submitter
Method: clinical testing
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IDUA-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004119854.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The IDUA c.208C>T variant is predicted to result in premature protein termination (p.Gln70*). This variant has been detected in the homozygous or compound heterozygous state … (more)
The IDUA c.208C>T variant is predicted to result in premature protein termination (p.Gln70*). This variant has been detected in the homozygous or compound heterozygous state in many individuals with mucopolysaccharidosis Type I (MPSI) and is among the most common causes of disease (Scott et al. 1992. PubMed ID: 1301941; Beesley et al. 2001. PubMed ID: 11735025; Pollard et al. 2013. PubMed ID: 22976768). This variant is reported in 0.19% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-981646-C-T). Nonsense variants in IDUA are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
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Pathogenic
(Aug 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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Mucopolysaccharidosis
Affected status: unknown
Allele origin:
germline
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Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV004239092.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
Comment:
This IDUA variant has been reported in several unrelated individuals with mucopolysaccharidosis type 1, either in the homozygous or compound heterozygous state. The variant (rs121965020) … (more)
This IDUA variant has been reported in several unrelated individuals with mucopolysaccharidosis type 1, either in the homozygous or compound heterozygous state. The variant (rs121965020) is rare (<0.1%) in a large population dataset (gnomAD v2.1.1: 137/274830 total alleles; 0.05%; no homozygotes), and has been reported in ClinVar (Variation ID 11909). This nonsense variant results in a premature stop codon in exon 2 of 14, likely leading to nonsense-mediated decay and lack of protein production, and this is supported by functional studies. We consider c.208C>T in IDUA to be pathogenic. (less)
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Pathogenic
(Jan 25, 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
|
Invitae
Accession: SCV000752528.8
First in ClinVar: Dec 06, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gln70*) in the IDUA gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Gln70*) in the IDUA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IDUA are known to be pathogenic (PMID: 11735025, 21480867). This variant is present in population databases (rs121965020, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 8401515, 21394825, 21831683, 22976768, 24314423, 24368159). ClinVar contains an entry for this variant (Variation ID: 11909). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001552737.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The IDUA p.Gln70X variant was identified in 69 of 500 proband chromosomes (frequency: 0.18) from individuals or families with Mucopolysaccharidosis type I (MPS I), and … (more)
The IDUA p.Gln70X variant was identified in 69 of 500 proband chromosomes (frequency: 0.18) from individuals or families with Mucopolysaccharidosis type I (MPS I), and was not identified in 40 control chromosomes from healthy individuals (Beesley_2001_11735025, Scott_1992_1505961, Vazna_2009_19396826, Yogalingam_2004_15300847, Bunge_1994_7951228, Pollard_2013_22976768). This variant was also identified in the following databases: dbSNP (ID: rs121965020) as “with Pathogenic allele-”, ClinVar (10x as pathogenic by EGL Genetic, Laboratory for Molecular Medicine , Illumina , Counsyl, Gene Reviews, OMIM, Children's Hospital of Philadelphia), Clinvitae (6x as pathogenic by ClinVar, EmvClass) and LOVD 3.0 (31x). This variant was identified in The NHLBI GO Exome Sequencing Project in 10 of 8592 European American alleles, (freq. 0.001), the Exome Aggregation Consortium database (August 8th 2016) in 72 of 110236 chromosomes (freq. 0.00065), the genome Aggregation Database (beta, October 19th 2016) in 142 of 270128 chromosomes (freq. 0.0005) in the following populations: African in 4 of 23548 chromosomes (freq. 0.00017), European Non Finnish in 85 of 121110 chromosomes (freq. 0.0007) and Finnish in 53 of 25426 chromosomes (freq. 0.002), but was not seen in other, Latino, Ashkenazi Jewish, East Asian and South Asian populations. Mucopolysaccharidosis type I (MPS I) is an autosomal recessive lysosomal storage disorder caused by a deficiency of a-L-iduronidase (IDUA). Mutations in the gene are responsible for the enzyme deficiency, which leads to the intralysosomal storage of the partially degraded glycosaminoglycans dermatan sulfate and heparin sulfate (Yogalingam_2004_15300847). The IDUA gene is approximately 19 kb in length. It maps to chromosome 4p16.3 and contains 14 exons, producing a transcript of 2.3 kb in length, which encodes a precursor protein consisting of 653 amino acids (8). The first 27 amino acids of the protein represent a signal peptide. To date, 199 different disease-causing IDUA gene mutations have been reported (9) (http://www.hgmd.org), with variable distribution across populations. Among them, p.W402X, p.Q70X, p.P533R, and p.G51D are the most common mutations worldwide (Atceken_2016_27511503). The p.Gln208X variant leads to a premature stop codon at position 70, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the IDUA gene are an established mechanism of disease in autosomal recessive Mucopolysaccharidosis type I disease and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. (less)
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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: SCV001970201.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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Pathogenic
(Nov 01, 2001)
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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: SCV000032919.3
First in ClinVar: Apr 04, 2013 Last updated: Apr 18, 2015 |
Comment on evidence:
By chemical cleavage followed by direct PCR sequencing, Scott et al. (1992) detected and characterized a nonsense mutation, a C-to-T transition at nucleotide 296, that … (more)
By chemical cleavage followed by direct PCR sequencing, Scott et al. (1992) detected and characterized a nonsense mutation, a C-to-T transition at nucleotide 296, that altered a gln codon at position 70 (CAG) to a stop codon (TAG). The termination of translation occurred soon after the mature 74-kD amino terminus of the IDUA protein. Using allele-specific oligonucleotides to detect mutations in a group of 73 MPS I patients, the authors found that the Q70X mutation accounted for 15% of all MPS I alleles. The mutation was associated with an extremely severe clinical phenotype in homozygotes. Patients who were compound heterozygotes showed a wide range of clinical phenotypes. Beesley et al. (2001) found that Q70X accounted for 15.9% of alleles in their large study. (less)
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Pathogenic
(Mar 04, 2015)
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no assertion criteria provided
Method: research
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Mucopolysaccharidosis Ih/s
Affected status: no
Allele origin:
germline
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Division of Human Genetics, Children's Hospital of Philadelphia
Study: CSER-PediSeq
Accession: SCV000238451.1 First in ClinVar: Jul 05, 2015 Last updated: Jul 05, 2015 |
Comment:
The IDUA variant (c.208C>T) is a nonsense mutation that is predicted to prematurely truncate the transcript, possibly leading to nonsense mediated decay. It has been … (more)
The IDUA variant (c.208C>T) is a nonsense mutation that is predicted to prematurely truncate the transcript, possibly leading to nonsense mediated decay. It has been identified in many patients in the literature and is the second most common pathogenic mutation in this gene, occurring in about 16% of affected individuals (Scott et al. 1992, PMID: 1301941; Beesley et al. 2001, PMID: 11735025; Pollard et al. 2007). Biochemical assays showed essentially no activity in homozygotes of this mutation (Oussoren et al. 2013, PMID: 23786846). The protein was also absent based on immunochemical analysis (Scott et al. 1992, PMID: 1301941). (less)
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Pathogenic
(Mar 04, 2015)
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no assertion criteria provided
Method: research
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Mucopolysaccharidosis Ih
Affected status: no
Allele origin:
germline
|
Division of Human Genetics, Children's Hospital of Philadelphia
Study: CSER-PediSeq
Accession: SCV000238450.1 First in ClinVar: Jul 05, 2015 Last updated: Jul 05, 2015 |
Comment:
The IDUA variant (c.208C>T) is a nonsense mutation that is predicted to prematurely truncate the transcript, possibly leading to nonsense mediated decay. It has been … (more)
The IDUA variant (c.208C>T) is a nonsense mutation that is predicted to prematurely truncate the transcript, possibly leading to nonsense mediated decay. It has been identified in many patients in the literature and is the second most common pathogenic mutation in this gene, occurring in about 16% of affected individuals (Scott et al. 1992, PMID: 1301941; Beesley et al. 2001, PMID: 11735025; Pollard et al. 2007). Biochemical assays showed essentially no activity in homozygotes of this mutation (Oussoren et al. 2013, PMID: 23786846). The protein was also absent based on immunochemical analysis (Scott et al. 1992, PMID: 1301941). (less)
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Pathogenic
(Mar 04, 2015)
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no assertion criteria provided
Method: research
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Mucopolysaccharidosis Is
Affected status: no
Allele origin:
germline
|
Division of Human Genetics, Children's Hospital of Philadelphia
Study: CSER-PediSeq
Accession: SCV000238452.1 First in ClinVar: Jul 05, 2015 Last updated: Jul 05, 2015 |
Comment:
The IDUA variant (c.208C>T) is a nonsense mutation that is predicted to prematurely truncate the transcript, possibly leading to nonsense mediated decay. It has been … (more)
The IDUA variant (c.208C>T) is a nonsense mutation that is predicted to prematurely truncate the transcript, possibly leading to nonsense mediated decay. It has been identified in many patients in the literature and is the second most common pathogenic mutation in this gene, occurring in about 16% of affected individuals (Scott et al. 1992, PMID: 1301941; Beesley et al. 2001, PMID: 11735025; Pollard et al. 2007). Biochemical assays showed essentially no activity in homozygotes of this mutation (Oussoren et al. 2013, PMID: 23786846). The protein was also absent based on immunochemical analysis (Scott et al. 1992, PMID: 1301941). (less)
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Pathogenic
(Sep 16, 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
|
Natera, Inc.
Accession: SCV001461747.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 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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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001806835.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 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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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001743657.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 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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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001926814.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 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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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: SCV001959623.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 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: SCV000264376.3
First in ClinVar: Sep 14, 2015 Last updated: Oct 01, 2022 |
Comment:
Common variant in Europe and Russia; associated with severe MPS I
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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 |
---|---|---|---|---|
Mucopolysaccharidosis Type I. | Adam MP | - | 2024 | PMID: 20301341 |
Worldwide distribution of common IDUA pathogenic variants. | Poletto E | Clinical genetics | 2018 | PMID: 29393969 |
IDUA mutational profile and genotype-phenotype relationships in UK patients with Mucopolysaccharidosis Type I. | Ghosh A | Human mutation | 2017 | PMID: 28752568 |
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 |
The great masquerade: delayed diagnosis of mucopolysaccharidosis in adulthood. | Kurniawan ED | Canadian journal of ophthalmology. Journal canadien d'ophtalmologie | 2013 | PMID: 24314423 |
Residual α-L-iduronidase activity in fibroblasts of mild to severe Mucopolysaccharidosis type I patients. | Oussoren E | Molecular genetics and metabolism | 2013 | PMID: 23786846 |
Molecular characterization of 355 mucopolysaccharidosis patients reveals 104 novel mutations. | Pollard LM | Journal of inherited metabolic disease | 2013 | PMID: 22976768 |
Mucopolysaccharidosis I mutations in Chinese patients: identification of 27 novel mutations and 6 cases involving prenatal diagnosis. | Wang X | Clinical genetics | 2012 | PMID: 21480867 |
A novel mucopolysaccharidosis type I associated splice site mutation and IDUA splice variants. | Bremer S | Molecular genetics and metabolism | 2011 | PMID: 21831683 |
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 |
Mucopolysaccharidosis type I in 21 Czech and Slovak patients: mutation analysis suggests a functional importance of C-terminus of the IDUA protein. | Vazna A | American journal of medical genetics. Part A | 2009 | PMID: 19396826 |
The prevalence of and survival in Mucopolysaccharidosis I: Hurler, Hurler-Scheie and Scheie syndromes in the UK. | Moore D | Orphanet journal of rare diseases | 2008 | PMID: 18796143 |
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 |
Gentamicin-mediated suppression of Hurler syndrome stop mutations restores a low level of alpha-L-iduronidase activity and reduces lysosomal glycosaminoglycan accumulation. | Keeling KM | Human molecular genetics | 2001 | PMID: 11159948 |
Analysis of five mutations in 20 mucopolysaccharidois type 1 patients: high prevalence of the W402X mutation. Mutations in brief no. 121. Online. | Gort L | Human mutation | 1998 | PMID: 10215409 |
Molecular genetics of mucopolysaccharidosis type I: mutation analysis among the patients of the former Soviet Union. | Voskoboeva EY | Molecular genetics and metabolism | 1998 | PMID: 9787109 |
Mutations among Italian mucopolysaccharidosis type I patients. | Gatti R | Journal of inherited metabolic disease | 1997 | PMID: 9427149 |
Mucopolysaccharidosis type I: identification of 8 novel mutations and determination of the frequency of the two common alpha-L-iduronidase mutations (W402X and Q70X) among European patients. | Bunge S | Human molecular genetics | 1994 | PMID: 7951228 |
Two novel mutations causing mucopolysaccharidosis type I detected by single strand conformational analysis of the alpha-L-iduronidase gene. | Clarke LA | Human molecular genetics | 1993 | PMID: 8401515 |
Structure and sequence of the human alpha-L-iduronidase gene. | Scott HS | Genomics | 1992 | PMID: 1505961 |
alpha-L-iduronidase mutations (Q70X and P533R) associate with a severe Hurler phenotype. | Scott HS | Human mutation | 1992 | PMID: 1301941 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=IDUA | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/a017198b-ddfd-4c42-816a-32aba115f584 | - | - | - | - |
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Text-mined citations for rs121965020 ...
HelpRecord last updated Jun 02, 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.