ClinVar Genomic variation as it relates to human health
NM_000203.5(IDUA):c.223G>A (p.Ala75Thr)
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.223G>A (p.Ala75Thr)
Variation ID: 222993 Accession: VCV000222993.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4p16.3 4: 987873 (GRCh38) [ NCBI UCSC ] 4: 981661 (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 Mar 6, 2016 Feb 14, 2024 Oct 15, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000203.5(IDUA):c.223G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
missense NM_000203.5:c.223G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000194.2:p.Ala75Thr missense NM_022042.4:c.*960C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
3 prime UTR NM_134425.4:c.576+3255C>T intron variant NM_213613.4:c.*960C>T 3 prime UTR NR_110313.1:n.311G>A non-coding transcript variant NC_000004.12:g.987873G>A NC_000004.11:g.981661G>A NG_008103.1:g.5877G>A NG_033042.1:g.10564C>T LRG_1277:g.5877G>A LRG_1277t1:c.223G>A LRG_1277p1:p.Ala75Thr P35475:p.Ala75Thr - Protein change
- A75T
- Other names
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- Canonical SPDI
- NC_000004.12:987872:G:A
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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.
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
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
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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 |
1390 | 2150 | |
SLC26A1 | - | - |
GRCh38 GRCh37 |
3 | 762 |
Conditions - Germline
Condition
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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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Oct 15, 2023 | RCV000208613.16 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 16, 2017 | RCV000670756.1 | |
Pathogenic (1) |
criteria provided, single submitter
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May 22, 2023 | RCV001781626.4 |
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
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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
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
(Nov 16, 2017)
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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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Counsyl
Accession: SCV000795651.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Pathogenic
(Mar 31, 2021)
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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: SCV001362838.2
First in ClinVar: Jun 22, 2020 Last updated: Apr 13, 2021 |
Comment:
Variant summary: IDUA c.223G>A (p.Ala75Thr) results in a non-conservative amino acid change located in the Glycoside hydrolase domain (IPR000514) of the encoded protein sequence. Four … (more)
Variant summary: IDUA c.223G>A (p.Ala75Thr) results in a non-conservative amino acid change located in the Glycoside hydrolase domain (IPR000514) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.3e-06 in 241700 control chromosomes. c.223G>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type 1 (example, Clarke_1994, Ghosh_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (example, Tieu_1995). Four clinical diagnostic laboratories and the Gene Reviews database have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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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: SCV001422947.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 01, 2022 |
Comment:
The p.Ala75Thr variant in IDUA has been reported in at least 9 individuals with mucopolysaccharidosis (MPS) (PMID: 29843745, 27146977, 28752568) and has been identified in … (more)
The p.Ala75Thr variant in IDUA has been reported in at least 9 individuals with mucopolysaccharidosis (MPS) (PMID: 29843745, 27146977, 28752568) and has been identified in 0.002% (3/121916) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs758452450). 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: 222993) as pathogenic by Counsyl and GeneReviews. 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 phenotype of individuals homozygous and compound heterozygous for this variant is highly specific for MPS based on null alpha-L-iduronidase activity, consistent with disease (PMID: 27146977). The presence of this variant in 3 affected homozygotes and in combination with reported pathogenic and likely pathogenic variants in 5 individuals with MPS increases the likelihood that the p.Ala75Thr variant is pathogenic (VariationID: 11908, 11909; PMID: 29843745, 27146977, 28752568). In summary, this variant meets criteria to be classified as pathogenic for MPS in an autosomal recessive manner based on the presence of the variant in combination with other pathogenic or likely pathogenic variants in individuals with MPS and the phenotype of individuals with the variant being highly specific for MPS. ACMG/AMP Criteria applied: PM3_very-strong, PM2, PP3, PP4 (Richards 2015). (less)
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Pathogenic
(May 22, 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: SCV002023093.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Oct 15, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001223842.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 75 of the IDUA protein (p.Ala75Thr). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 75 of the IDUA protein (p.Ala75Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 8680403, 11735025, 16438163, 27146977, 29843745). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 222993). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on IDUA protein function. Experimental studies have shown that this missense change affects IDUA function (PMID: 7550232). For these reasons, this variant has been classified as Pathogenic. (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
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Natera, Inc.
Accession: SCV001461748.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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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Novel splice site IDUA gene mutation in Tunisian pedigrees with hurler syndrome. | Chkioua L | Diagnostic pathology | 2018 | PMID: 29843745 |
IDUA mutational profile and genotype-phenotype relationships in UK patients with Mucopolysaccharidosis Type I. | Ghosh A | Human mutation | 2017 | PMID: 28752568 |
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 |
The molecular basis of mucopolysaccharidosis type I in two Thai patients. | Ketudat Cairns JR | The Southeast Asian journal of tropical medicine and public health | 2005 | PMID: 16438163 |
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 |
Molecular genetics of mucopolysaccharidosis type I: diagnostic, clinical, and biological implications. | Scott HS | Human mutation | 1995 | PMID: 8680403 |
Four novel mutations underlying mild or intermediate forms of alpha-L-iduronidase deficiency (MPS IS and MPS IH/S). | Tieu PT | Human mutation | 1995 | PMID: 7550232 |
Mutation analysis of 19 North American mucopolysaccharidosis type I patients: identification of two additional frequent mutations. | Clarke LA | Human mutation | 1994 | PMID: 8019563 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/530c09fc-6d05-4751-82a7-67d3de801705 | - | - | - | - |
Text-mined citations for rs758452450 ...
HelpRecord last updated Sep 29, 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.