ClinVar Genomic variation as it relates to human health
NM_000203.5(IDUA):c.1037T>G (p.Leu346Arg)
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.1037T>G (p.Leu346Arg)
Variation ID: 11927 Accession: VCV000011927.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4p16.3 4: 1002333 (GRCh38) [ NCBI UCSC ] 4: 996121 (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 Sep 18, 2016 Feb 14, 2024 Jan 2, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000203.5:c.1037T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000194.2:p.Leu346Arg missense NM_001363576.1:c.641T>G NP_001350505.1:p.Leu214Arg missense NR_110313.1:n.1125T>G non-coding transcript variant NC_000004.12:g.1002333T>G NC_000004.11:g.996121T>G NG_008103.1:g.20337T>G LRG_1277:g.20337T>G LRG_1277t1:c.1037T>G LRG_1277p1:p.Leu346Arg P35475:p.Leu346Arg - Protein change
- L346R, L214R
- Other names
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- Canonical SPDI
- NC_000004.12:1002332:T: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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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IDUA | - | - |
GRCh38 GRCh37 |
1383 | 2117 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
no assertion criteria provided
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Dec 1, 2004 | RCV000012702.27 | |
Pathogenic (2) |
criteria provided, single submitter
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Nov 2, 2017 | RCV000012703.17 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 2, 2024 | RCV001248726.12 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Jan 02, 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: SCV001422232.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 346 of the IDUA protein (p.Leu346Arg). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 346 of the IDUA protein (p.Leu346Arg). This variant is present in population databases (rs121965033, gnomAD 0.006%). This missense change has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 10735634, 15521993, 21480867, 21624210, 29801497). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of East Asian ancestry (PMID: 10735634, 15521993, 21480867, 21624210, 29801497). ClinVar contains an entry for this variant (Variation ID: 11927). 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: 10735634). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 02, 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: SCV000795251.1
First in ClinVar: Sep 18, 2016 Last updated: Sep 18, 2016 |
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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: SCV001422673.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 01, 2022 |
Comment:
The p.Leu346Arg variant in IDUA has been reported in at least 19 individuals with mucopolysaccharidosis (MPS) (PMID: 10735634, 21480867, 27520059) and has been identified in … (more)
The p.Leu346Arg variant in IDUA has been reported in at least 19 individuals with mucopolysaccharidosis (MPS) (PMID: 10735634, 21480867, 27520059) and has been identified in 0.006% (1/18160) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121965033). 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: 11927) as pathogenic by Counsyl and OMIM. In vitro functional studies provide some evidence that the p.Leu346Arg variant may impact protein function (PMID: 10735634). 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 phenotype of individuals compound heterozygous for this variant is highly specific for MPS based on alpha-L-iduronidase activity being <1% consistent with disease (PMID: 21480867). The presence of this variant in 4 affected homozygotes and in combination with reported pathogenic or likely pathogenic variants in 5 individuals with MPS1 increases the likelihood that the p.Leu346Arg variant is pathogenic (VariationID: 551563, 11921; PMID: 10735634, 21480867, 27520059). 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 the homozygous state and in combination with other pathogenic variants in individuals with MPS, functional studies, and the phenotype of individuals with the variant being highly specific for MPS. ACMG/AMP Criteria applied: PM3_very-strong, PS3, PM2, PP3, PP4 (Richards 2015). (less)
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Pathogenic
(Dec 01, 2004)
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no assertion criteria provided
Method: literature only
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HURLER-SCHEIE SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000032937.4
First in ClinVar: Apr 04, 2013 Last updated: Sep 14, 2020 |
Comment on evidence:
For discussion of the leu346-to-arg (L346R) mutation in the IDUA gene that was found in compound heterozygous state in a patient with Hurler/Scheie syndrome (607015) … (more)
For discussion of the leu346-to-arg (L346R) mutation in the IDUA gene that was found in compound heterozygous state in a patient with Hurler/Scheie syndrome (607015) by Teng et al. (2000), see 252800.0019. Lee et al. (2004) found the L346R mutation in 6 of 10 unrelated Korean patients with MPS I, 4 with Hurler syndrome (607014) and 2 with Hurler/Scheie syndrome. (less)
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Pathogenic
(Dec 01, 2004)
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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: SCV000032938.4
First in ClinVar: Apr 04, 2013 Last updated: Sep 14, 2020 |
Comment on evidence:
For discussion of the leu346-to-arg (L346R) mutation in the IDUA gene that was found in compound heterozygous state in a patient with Hurler/Scheie syndrome (607015) … (more)
For discussion of the leu346-to-arg (L346R) mutation in the IDUA gene that was found in compound heterozygous state in a patient with Hurler/Scheie syndrome (607015) by Teng et al. (2000), see 252800.0019. Lee et al. (2004) found the L346R mutation in 6 of 10 unrelated Korean patients with MPS I, 4 with Hurler syndrome (607014) and 2 with Hurler/Scheie syndrome. (less)
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Pathogenic
(Dec 10, 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: SCV002075329.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Status of newborn screening and follow up investigations for Mucopolysaccharidoses I and II in Taiwan. | Chuang CK | Orphanet journal of rare diseases | 2018 | PMID: 29801497 |
Report of 5 novel mutations of the α-L-iduronidase gene and comparison of Korean mutations in relation with those of Japan or China in patients with mucopolysaccharidosis I. | Kwak MJ | BMC medical genetics | 2016 | PMID: 27520059 |
Mucopolysaccharidosis I mutations in Chinese patients: identification of 27 novel mutations and 6 cases involving prenatal diagnosis. | Wang X | Clinical genetics | 2012 | PMID: 21480867 |
[Mutation analysis and prenatal diagnosis of 2 cases with mucopolysaccharidosis type I]. | Wang XN | Zhonghua er ke za zhi = Chinese journal of pediatrics | 2011 | PMID: 21624210 |
Mutational analysis of the alpha-L-iduronidase gene in 10 unrelated Korean type I mucopolysaccharidosis patients: Identification of four novel mutations. | Lee IJ | Clinical genetics | 2004 | PMID: 15521993 |
Identification and characterization of -3c-g acceptor splice site mutation in human alpha-L-iduronidase associated with mucopolysaccharidosis type IH/S. | Teng YN | Clinical genetics | 2000 | PMID: 10735634 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/d33cd08d-b32d-48e3-bd29-eb363ce53e7e | - | - | - | - |
Text-mined citations for rs121965033 ...
HelpRecord last updated Mar 30, 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.