The p.Asp349Asn variant in IDUA has been reported in 2 individuals with mucopolysaccharidosis (MPS) (PMID: 1627351, 8680403) and has been identified in 0.006% (1/15972) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs368454909). 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: 92623) as pathogenic by EGL Genetic Diagnostics. In vitro functional studies provide some evidence that the p.Asp349Asn variant may impact protein function (PMID: 1627351). 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 presence of this variant in combination with a reported pathogenic variant in an individual with MPS increases the likelihood that the p.Asp349Asn variant is pathogenic (VariationID: 11909; PMID: 8680403). This variant is located in a region of IDUA that is essential to substrate binding, suggesting that this variant is in a functional domain and supports pathogenicity (PMID: 24036510, 23959878, 1627351). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM1, PS3_moderate, PP3, PM3_supporting (Richards 2015).
ClinVar Genomic variation as it relates to human health
NM_000203.5(IDUA):c.1045G>A (p.Asp349Asn)
Germline
Classification
Help
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.
(4)
Help
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.
Pathogenic/Likely pathogenic
4
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000203.5(IDUA):c.1045G>A (p.Asp349Asn)
Variation ID: 92623 Accession: VCV000092623.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4p16.3 4: 1002341 (GRCh38) [ NCBI UCSC ] 4: 996129 (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 Jun 28, 2015 Feb 14, 2024 Dec 18, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000203.5:c.1045G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000194.2:p.Asp349Asn missense NM_001363576.1:c.649G>A NP_001350505.1:p.Asp217Asn missense NR_110313.1:n.1133G>A non-coding transcript variant NC_000004.12:g.1002341G>A NC_000004.11:g.996129G>A NG_008103.1:g.20345G>A LRG_1277:g.20345G>A LRG_1277t1:c.1045G>A LRG_1277p1:p.Asp349Asn P35475:p.Asp349Asn - Protein change
- D349N, D217N
- Other names
- -
- Canonical SPDI
- NC_000004.12:1002340: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
Help
The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| IDUA | - | - |
GRCh38 GRCh37 |
1390 | 2153 | |
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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 18, 2023 | RCV000180110.16 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Apr 22, 2023 | RCV001248916.18 |
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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|---|---|---|---|---|---|
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Pathogenic
(Nov 30, 2012)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000232486.5
First in ClinVar: Jun 28, 2015 Last updated: Jun 28, 2015 |
Number of individuals with the variant: 1
Sex: mixed
|
|
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Likely pathogenic
(Dec 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002016683.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
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Likely pathogenic
(Jan 14, 2020)
|
criteria provided, single submitter
Method: curation
|
Mucopolysaccharidosis type 1
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001422672.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 05, 2022 |
Comment:
The p.Asp349Asn variant in IDUA has been reported in 2 individuals with mucopolysaccharidosis (MPS) (PMID: 1627351, 8680403) and has been identified in 0.006% (1/15972) of … (more)
The p.Asp349Asn variant in IDUA has been reported in 2 individuals with mucopolysaccharidosis (MPS) (PMID: 1627351, 8680403) and has been identified in 0.006% (1/15972) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs368454909). 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: 92623) as pathogenic by EGL Genetic Diagnostics. In vitro functional studies provide some evidence that the p.Asp349Asn variant may impact protein function (PMID: 1627351). 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 presence of this variant in combination with a reported pathogenic variant in an individual with MPS increases the likelihood that the p.Asp349Asn variant is pathogenic (VariationID: 11909; PMID: 8680403). This variant is located in a region of IDUA that is essential to substrate binding, suggesting that this variant is in a functional domain and supports pathogenicity (PMID: 24036510, 23959878, 1627351). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM1, PS3_moderate, PP3, PM3_supporting (Richards 2015). (less)
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Pathogenic
(Apr 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Mucopolysaccharidosis type 1
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001576109.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp349 amino acid residue in IDUA. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp349 amino acid residue in IDUA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12203999, 12559846). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt IDUA protein function. ClinVar contains an entry for this variant (Variation ID: 92623). This missense change has been observed in individuals with mucopolysaccharidosis type I (PMID: 8680403, 31194252). 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 sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 349 of the IDUA protein (p.Asp349Asn). (less)
|
Comment:
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp349 amino acid residue in IDUA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12203999, 12559846). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt IDUA protein function. ClinVar contains an entry for this variant (Variation ID: 92623). This missense change has been observed in individuals with mucopolysaccharidosis type I (PMID: 8680403, 31194252). 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 sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 349 of the IDUA protein (p.Asp349Asn).
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. |
Comment:
The p.Asp349Asn variant in IDUA has been reported in 2 individuals with mucopolysaccharidosis (MPS) (PMID: 1627351, 8680403) and has been identified in 0.006% (1/15972) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs368454909). 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: 92623) as pathogenic by EGL Genetic Diagnostics. In vitro functional studies provide some evidence that the p.Asp349Asn variant may impact protein function (PMID: 1627351). 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 presence of this variant in combination with a reported pathogenic variant in an individual with MPS increases the likelihood that the p.Asp349Asn variant is pathogenic (VariationID: 11909; PMID: 8680403). This variant is located in a region of IDUA that is essential to substrate binding, suggesting that this variant is in a functional domain and supports pathogenicity (PMID: 24036510, 23959878, 1627351). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM1, PS3_moderate, PP3, PM3_supporting (Richards 2015).
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp349 amino acid residue in IDUA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12203999, 12559846). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt IDUA protein function. ClinVar contains an entry for this variant (Variation ID: 92623). This missense change has been observed in individuals with mucopolysaccharidosis type I (PMID: 8680403, 31194252). 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 sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 349 of the IDUA protein (p.Asp349Asn).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genotype-phenotype relationships in mucopolysaccharidosis type I (MPS I): Insights from the International MPS I Registry. | Clarke LA | Clinical genetics | 2019 | PMID: 31194252 |
| Insights into mucopolysaccharidosis I from the structure and action of α-L-iduronidase. | Bie H | Nature chemical biology | 2013 | PMID: 24036510 |
| Human α-L-iduronidase uses its own N-glycan as a substrate-binding and catalytic module. | Maita N | Proceedings of the National Academy of Sciences of the United States of America | 2013 | PMID: 23959878 |
| Identification and characterization of 13 new mutations in mucopolysaccharidosis type I patients. | Matte U | Molecular genetics and metabolism | 2003 | PMID: 12559846 |
| Molecular analysis of 30 mucopolysaccharidosis type I patients: evaluation of the mutational spectrum in Italian population and identification of 13 novel mutations. | Venturi N | Human mutation | 2002 | PMID: 12203999 |
| Molecular genetics of mucopolysaccharidosis type I: diagnostic, clinical, and biological implications. | Scott HS | Human mutation | 1995 | PMID: 8680403 |
| Hurler syndrome: a patient with abnormally high levels of alpha-L-iduronidase protein. | Brooks DA | Biochemical medicine and metabolic biology | 1992 | PMID: 1627351 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=IDUA | - | - | - | - |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/6669da7c-3819-4856-940e-d9107f1bf2bc | - | - | - | - |
Text-mined citations for rs368454909 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 10, 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.