The c.1205G>A (p.Trp402ter) nonsense variant in the IDUA gene is the most common variant reported in individuals affected with Hurler Syndrome (Scott et al., 1992; Pollard et al., 2013; Leroux et al., 2014). The p.Trp402ter variant is predicted to cause a protein termination in exon 9 (out of a total of 14 exons in the coding sequence). Nonsense variants have been described in the IDUA gene in several affected individuals (Scott et al., 1992; Pollard et al., 2013) and are, therefore, a common mechanism of disease. Multiple in vivo functional studies have demonstrated the p.Trp402ter variant results in IDUA deficiency (Scott et al., 1992; Wang et al., 2009; Oussoren et al., 2013). This c.1205G>A variant has not been reported in the three population databases (Exome Sequencing Project [ESP], 1000 Genomes, and ExAC). Multiple in silico algorithms predict this variant to have a deleterious effect (GERP = 4.86; CADD = 41), and reputable diagnostic laboratories have reported this variant as pathogenic. IDUA is the only gene in which pathogenic variants are known to cause Hurler Syndrome. Therefore, this collective evidence supports the classification of the c.1205G>A (p.Trp402ter) as a Pathogenic variant for Hurler Syndrome.
ClinVar Genomic variation as it relates to human health
NM_000203.5(IDUA):c.1205G>A (p.Trp402Ter)
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.
(30)
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
30
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.1205G>A (p.Trp402Ter)
Variation ID: 11908 Accession: VCV000011908.82
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 4p16.3 4: 1002747 (GRCh38) [ NCBI UCSC ] 4: 996535 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Oct 20, 2024 Mar 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000203.5:c.1205G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000194.2:p.Trp402Ter nonsense NM_001363576.1:c.809G>A NP_001350505.1:p.Trp270Ter nonsense NR_110313.1:n.1293G>A non-coding transcript variant NC_000004.12:g.1002747G>A NC_000004.11:g.996535G>A NG_008103.1:g.20751G>A LRG_1277:g.20751G>A LRG_1277t1:c.1205G>A LRG_1277p1:p.Trp402Ter - Protein change
- W402*, W270*
- Other names
- -
- Canonical SPDI
- NC_000004.12:1002746:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
-
0.00040 (A)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00000
1000 Genomes Project 0.00040
The Genome Aggregation Database (gnomAD), exomes 0.00059
1000 Genomes Project 30x 0.00062
Trans-Omics for Precision Medicine (TOPMed) 0.00083
The Genome Aggregation Database (gnomAD) 0.00086
- 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 (4) |
criteria provided, multiple submitters, no conflicts
|
Feb 13, 2024 | RCV000012683.46 | |
| Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
Mar 1, 2024 | RCV000078374.47 | |
| Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
Jan 29, 2024 | RCV000384297.38 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Dec 29, 2021 | RCV000477890.20 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 3, 2018 | RCV001004934.11 | |
|
See cases
|
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 3, 2024 | RCV002251896.11 |
|
IDUA-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Jun 18, 2024 | RCV003398488.6 |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 29, 2022 | RCV002512986.9 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Jan 27, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Hurler syndrome
Affected status: no
Allele origin:
germline
|
Knight Diagnostic Laboratories, Oregon Health and Sciences University
Study: CSER-NextGen
Accession: SCV000538044.1 First in ClinVar: Apr 03, 2017 Last updated: Apr 03, 2017 |
Comment:
The c.1205G>A (p.Trp402ter) nonsense variant in the IDUA gene is the most common variant reported in individuals affected with Hurler Syndrome (Scott et al., 1992; … (more)
The c.1205G>A (p.Trp402ter) nonsense variant in the IDUA gene is the most common variant reported in individuals affected with Hurler Syndrome (Scott et al., 1992; Pollard et al., 2013; Leroux et al., 2014). The p.Trp402ter variant is predicted to cause a protein termination in exon 9 (out of a total of 14 exons in the coding sequence). Nonsense variants have been described in the IDUA gene in several affected individuals (Scott et al., 1992; Pollard et al., 2013) and are, therefore, a common mechanism of disease. Multiple in vivo functional studies have demonstrated the p.Trp402ter variant results in IDUA deficiency (Scott et al., 1992; Wang et al., 2009; Oussoren et al., 2013). This c.1205G>A variant has not been reported in the three population databases (Exome Sequencing Project [ESP], 1000 Genomes, and ExAC). Multiple in silico algorithms predict this variant to have a deleterious effect (GERP = 4.86; CADD = 41), and reputable diagnostic laboratories have reported this variant as pathogenic. IDUA is the only gene in which pathogenic variants are known to cause Hurler Syndrome. Therefore, this collective evidence supports the classification of the c.1205G>A (p.Trp402ter) as a Pathogenic variant for Hurler Syndrome. (less)
|
|
|
Pathogenic
(Jan 01, 2019)
|
criteria provided, single submitter
Method: literature only
|
Mucopolysaccharidosis type I
Affected status: yes
Allele origin:
germline
|
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova
Accession: SCV000929875.1
First in ClinVar: Jul 30, 2019 Last updated: Jul 30, 2019 |
Comment:
PVS1: nonsense. PP1: Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease. PM2: Very low frequency in … (more)
PVS1: nonsense. PP1: Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease. PM2: Very low frequency in GnomAD (less)
|
|
|
Pathogenic
(Mar 31, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000232926.5
First in ClinVar: Jun 28, 2015 Last updated: Jul 30, 2019 |
Number of individuals with the variant: 98
Sex: mixed
|
|
|
Pathogenic
(May 16, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Mucopolysaccharidosis type 1
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000712125.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
The p.Trp402X variant in IDUA has been reported in several individuals with muco polysaccharidosis type I (MPS-I) and has been associated with the severe Hurler … (more)
The p.Trp402X variant in IDUA has been reported in several individuals with muco polysaccharidosis type I (MPS-I) and has been associated with the severe Hurler syndrome phenotype in the homozygous state (Scott 1992, Pollard 2013, Cobos 2015 , Ahmed 2014, Oussoren 2013, Leroux 2014). It was absent form large population s tudies. This nonsense variant leads to a premature termination codon at positio n 402, which is predicted to lead to a truncated or absent protein. In mouse mod els, this variant led to phenotypes associated with the disease (Wang 2010). In summary, the p.Trp402X variant meets our criteria to be classified as pathogenic for mucopolysaccharidosis type I in an autosomal recessive manner, based upon i ts identification with patients, predicted functional impact and animal model st udies. (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Nov 12, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Hurler syndrome
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV001193947.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020 |
Comment:
NM_000203.3(IDUA):c.1205G>A(W402*) is classified as pathogenic in the context of mucopolysaccharidosis type I. Sources cited for classification include the following: PMID 1301196, 21394825, 7951228 and 11735025. … (more)
NM_000203.3(IDUA):c.1205G>A(W402*) is classified as pathogenic in the context of mucopolysaccharidosis type I. Sources cited for classification include the following: PMID 1301196, 21394825, 7951228 and 11735025. Classification of NM_000203.3(IDUA):c.1205G>A(W402*) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
|
|
|
Pathogenic
(Sep 15, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Hurler syndrome
Mucopolysaccharidosis, MPS-I-H/S Mucopolysaccharidosis, MPS-I-S
Affected status: yes
Allele origin:
germline
|
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital
Accession: SCV001423593.1
First in ClinVar: Jul 27, 2020 Last updated: Jul 27, 2020 |
Comment:
[ACMG/AMP: PVS1, PS3, PS4_Moderate, PP5] This alteration is a null variant in a gene where LOF is a known mechanism of disease [PVS1], is supported … (more)
[ACMG/AMP: PVS1, PS3, PS4_Moderate, PP5] This alteration is a null variant in a gene where LOF is a known mechanism of disease [PVS1], is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3], has previously been observed in multiple unrelated patients with the same phenotype [PS4_Moderate], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5]. (less)
|
|
|
Pathogenic
(Jul 08, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Mucopolysaccharidosis Ih/s
Affected status: yes
Allele origin:
germline
|
Knight Diagnostic Laboratories, Oregon Health and Sciences University
Accession: SCV001448767.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 1
Clinical Features:
Increased antibody level in blood (present) , Hypoalbuminemia (present) , Lymphadenopathy (present) , Vertebral compression fractures (present) , Aseptic necrosis (present) , Myelodysplasia (present) , … (more)
Increased antibody level in blood (present) , Hypoalbuminemia (present) , Lymphadenopathy (present) , Vertebral compression fractures (present) , Aseptic necrosis (present) , Myelodysplasia (present) , Failure to thrive (present) , Short stature (present) , Proptosis (present) , Thrombocytosis (present) , Normocytic anemia (present) , Neutropenia (present) , Hepatosplenomegaly (present) , Hepatic fibrosis (present) , Hypersplenism (present) (less)
Sex: male
|
|
|
Pathogenic
(Nov 03, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002010071.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
|
|
|
Pathogenic
(Jan 12, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002023115.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jun 29, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV003559978.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The c.1205G>A (p.W402*) alteration, located in exon 9 (coding exon 9) of the IDUA gene, consists of a G to A substitution at nucleotide position … (more)
The c.1205G>A (p.W402*) alteration, located in exon 9 (coding exon 9) of the IDUA gene, consists of a G to A substitution at nucleotide position 1205. This changes the amino acid from a tryptophan (W) to a stop codon at amino acid position 402. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration has been detected in the homozygous state, and in conjunction with a pathogenic IDUA mutation, in multiple individuals with mucopolysaccharidosis type I (MPS1) (Gort, 1998; Scott, 1992; Li, 2002; Bush, 2019; Guffon, 2021). Based on the available evidence, this alteration is classified as pathogenic. (less)
|
|
|
Pathogenic
(Jul 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
see cases
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University Hospital Muenster
Accession: SCV002506433.2
First in ClinVar: May 07, 2022 Last updated: Jul 07, 2024 |
Comment:
ACMG categories: PVS1,PM2,PP3,PP5
Number of individuals with the variant: 1
Clinical Features:
Mucopolysacchariduria (present)
Age: 70-79 years
Sex: male
Tissue: blood
|
|
|
Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hurler syndrome
Mucopolysaccharidosis, MPS-I-H/S Mucopolysaccharidosis, MPS-I-S
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000894345.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
|
Pathogenic
(Oct 23, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Mucopolysaccharidosis type I
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000451787.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The IDUA c.1205G>A (p.Trp402Ter) variant is a stop-gained variant and is well described in the literature as a pathogenic variant associated with mucopolysaccharidosis type I, … (more)
The IDUA c.1205G>A (p.Trp402Ter) variant is a stop-gained variant and is well described in the literature as a pathogenic variant associated with mucopolysaccharidosis type I, accounting for 37% of disease alleles in Europeans, 43% in North Americans of European ancestry, and 55% of Australasians (Clarke et al. 2016). The p.Trp402Ter variant has been reported in at least seven studies in which it is found in a total of at least 30 individuals with mucopolysaccharidosis type I, including in 12 in a homozygous state, in at least 17 in a compound heterozygous state, and in one in a heterozygous state where a second variant was not identified. The variant was also found in an additional 93 of 298 disease alleles of unspecified zygosity (Scott et al. 1992; Beesley et al. 2001; Pollard et al. 2013; Oussoren et al. 2013; Ahmed et al. 2014; Leroux et al. 2014; Atceken et al. 2016). The p.Trp402Ter variant was absent from 20 control alleles but is reported at a frequency of 0.00045 in the combined European American and African American populations of the Exome Sequencing Project. Functional studies demonstrated that the variant resulted in low or undetectable IDUA activity in the homozygous state and 50% activity in the heterozygous state in human and mouse (Scott et al. 1992; Beesley et al. 2001; Wang et al. 2010; Oussoren et al. 2013; Leroux et al. 2014). Due to the potential impact of stop-gained variants and the supporting evidence, the p.Trp402Ter 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)
|
|
|
Pathogenic
(Dec 03, 2018)
|
criteria provided, single submitter
Method: research
|
Mucopolysaccharidosis, MPS-I-H/S
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001164454.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
Comment:
The heterozygous p.Trp402Ter 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.Trp402Ter variant in IDUA was identified by our study in the compound heterozygous state, with another pathogenic variant, in one individual with Hurler-Scheie syndrome. This variant was absent from large population studies. This nonsense variant leads to a premature termination codon at position 402, 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. This variant has also been reported pathogenic in ClinVar (Variation ID: 11908) and is a well-known pathogenic variant in individuals with Hurler-Scheie syndrome that was reported in the homozygous and heterozygous state (86/200 alleles) of individuals with Hurler-Scheie syndrome from two cohorts (PMID: 22976768, 29393969, 11735025). 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)
|
|
|
Pathogenic
(Dec 17, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Mucopolysaccharidosis type 1
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000695969.2
First in ClinVar: Dec 26, 2017 Last updated: Jun 22, 2020 |
Comment:
Variant summary: IDUA c.1205G>A (p.Trp402X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: IDUA c.1205G>A (p.Trp402X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00059 in 90548 control chromosomes. c.1205G>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type 1 and is reported as one of the most common pathogenic variants causing Mucopolysaccharidosis type I. Clinical and functional data are consistent with the pathogenic outcome for the variant. 11 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Dec 11, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000329822.7
First in ClinVar: Dec 06, 2016 Last updated: Jul 24, 2021 |
Comment:
One of the most common pathogenic variants identified in European and American individuals with mucopolysaccharidosis type I, accounting for 17-48% of pathogenic variants in these … (more)
One of the most common pathogenic variants identified in European and American individuals with mucopolysaccharidosis type I, accounting for 17-48% of pathogenic variants in these populations (Bunge et al., 1994; Beesley et al., 2001; Pollard et al., 2013); 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: 32371413, 31980526, 32670797, 7951228, 30548430, 29654546, 1301196, 22976768, 26965916, 27511503, 15081804, 21364962, 8213840, 12509712, 8554071, 9427149, 11735025, 25525159, 19751987, 24368159, 23786846, 24698225, 30609409) (less)
|
|
|
Pathogenic
(Jan 13, 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: SCV001422680.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 05, 2022 |
Comment:
The p.Trp402Ter variant in IDUA has been reported in at least 85 individuals with mucopolysaccharidosis (MSP) (PMID: 28752568, 10215409) and has been identified in 0.142% … (more)
The p.Trp402Ter variant in IDUA has been reported in at least 85 individuals with mucopolysaccharidosis (MSP) (PMID: 28752568, 10215409) and has been identified in 0.142% (69/48650) of European (non-Finnish) chromosomes, 0.046% (9/19442) of Latino chromosomes, and 0.034% (3/8772) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121965019). 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: 11908) as pathogenic by 12 submitters. Animal models in mice have shown that this variant causes MSP (doi: 10.1016/j.ymgme.2014.12.026). This nonsense variant leads to a premature termination codon at position 402, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the IDUA gene is an established disease mechanism in MSP. The phenotype of individuals compound heterozygous for this variant is highly specific for MSP based on very low alpha-L-iduronidase activity consistent with disease (PMID: 28752568). The presence of this variant in 38 affected homozygotes and in combination with reported pathogenic variants in at least 38 affected individuals increases the likelihood that the p.Trp402Ter variant is pathogenic (VariationID: 222996, 11909, 167190; PMID: 28752568, 10215409). In summary, this variant meets criteria to be classified as pathogenic for MSP in an autosomal recessive manner based on the prediction that it will cause loss of function, mouse models, and the presence of the variant in affected homozygotes. ACMG/AMP Criteria applied: PVS1, PM3_very-strong, PS3, PP4 (Richards 2015). (less)
|
|
|
Pathogenic
(Dec 29, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hurler syndrome
Mucopolysaccharidosis, MPS-I-H/S Mucopolysaccharidosis, MPS-I-S
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV002061789.2
First in ClinVar: Jan 22, 2022 Last updated: Feb 13, 2022 |
Comment:
PVS1, PS3, PP1, PM3
|
|
|
Pathogenic
(Sep 13, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV002525757.1
First in ClinVar: Jun 11, 2022 Last updated: Jun 11, 2022 |
|
|
|
Pathogenic
(Jan 03, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
See cases
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002522896.2
First in ClinVar: Jun 11, 2022 Last updated: Jan 06, 2024 |
Comment:
ACMG classification criteria: PVS1, PM2_supporting, PM3, PP4
Clinical Features:
Obesity (present) , Hernia of the abdominal wall (present) , Short stature (present) , Hypospadias (present) , Global developmental delay (present) , Neurodevelopmental abnormality (present) … (more)
Obesity (present) , Hernia of the abdominal wall (present) , Short stature (present) , Hypospadias (present) , Global developmental delay (present) , Neurodevelopmental abnormality (present) , Hypogonadism (present) , Abnormal size of pituitary gland (present) (less)
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Pathogenic
(Jan 29, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000627147.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Trp402*) 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.Trp402*) 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 (rs121965019, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individuals with mucopolysaccharidosis type I (PMID: 1301196, 11735025, 20301341, 21394825, 22976768). ClinVar contains an entry for this variant (Variation ID: 11908). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 13, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hurler syndrome
Affected status: unknown
Allele origin:
germline
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Clinical Genomics Laboratory, Washington University in St. Louis
Accession: SCV005045018.1
First in ClinVar: May 26, 2024 Last updated: May 26, 2024 |
Comment:
The IDUA c.1205G>A (p.Trp402Ter) variant is the most common reported variant in individuals affected with mucopolysaccharidosis I. This variant has been observed in both a … (more)
The IDUA c.1205G>A (p.Trp402Ter) variant is the most common reported variant in individuals affected with mucopolysaccharidosis I. This variant has been observed in both a homozygous and compound heterozygous state in affected individuals (Beesley CE et al., PMID: 11735025; Bertola F et al., PMID: 21394825; Gort L et al., PMID: 10215409; Pollard LM et al., PMID: 22976768; Scott HS et al., PMID: 1301196). This variant causes a stop gain, which is predicted to lead to nonsense mediated decay. In vivo mouse studies modeling this variant show no detectable alpha-L-iduronidase activity, indicating that this variant impacts protein function (Wang D et al., PMID: 19751987). The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 0.14% in the European non-Finnish population. This variant has been reported in the ClinVar database as a germline pathogenic variant by ten submitters. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. (less)
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Pathogenic
(Mar 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: SCV001748089.20
First in ClinVar: Jul 10, 2021 Last updated: Oct 20, 2024 |
Comment:
IDUA: PM3:Very Strong, PVS1, PM2
Number of individuals with the variant: 3
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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: SCV000032918.3
First in ClinVar: Apr 04, 2013 Last updated: Apr 18, 2015 |
Comment on evidence:
Scott et al. (1992) found that 31% of MPS I alleles in a study of 64 patients with Hurler syndrome (607014) had a trp402-to-ter (W402X) … (more)
Scott et al. (1992) found that 31% of MPS I alleles in a study of 64 patients with Hurler syndrome (607014) had a trp402-to-ter (W402X) substitution in the alpha-L-iduronidase protein associated with very severe clinical phenotype in homozygotes. A G-to-A transition at nucleotide 1293 altered the W402 codon (TGG) to a stop codon (TAG); translation was terminated approximately two-thirds of the way through the 653-amino acid IDUA protein. The mutation was originally detected by chemical cleavage and then by direct PCR sequencing. The patients who were compound heterozygotes for the allele had a wide range of clinical phenotypes. Based on polymorphisms within the IDUA gene, Scott et al. (1992) determined that the W402X mutation is associated with 3 different haplotypes, implying more than one origin for the mutation or intragenic recombination. The mutation introduced a MaeI restriction endonuclease site into the gene, thus enabling simple detection of the mutation. Assessment of the efficacy of bone marrow transplantation in patients homozygous for the mutation is thus possible. Significantly, the index case of Scheie syndrome (GM1323) reported by McKusick et al. (1965), who had been assumed to be a homozygote for a separate allele at the IDUA locus, was found in fact to be a compound heterozygote for the W402X allele. Biochemically, following the use of 2 different IDUA monoclonal antibodies, GM1323 fibroblasts had no detectable IDUA protein. They had approximately 0.3% of IDUA activity. This IDUA activity must result from a mild mutation in the other MPS I allele present in the patient. Subsequently, with definition of the mutation in the other allele (252800.0004), this proved to be the case. Beesley et al. (2001) found that W402X accounted for 45.3% of mutant alleles in their study. (less)
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Pathogenic
(May 14, 2015)
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no assertion criteria provided
Method: research
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Mucopolysaccharidosis, MPS-I-S
Hurler syndrome Mucopolysaccharidosis, MPS-I-H/S
Affected status: unknown
Allele origin:
germline
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Division of Human Genetics, Children's Hospital of Philadelphia
Study: CSER-PediSeq
Accession: SCV000536710.1 First in ClinVar: Apr 23, 2017 Last updated: Apr 23, 2017 |
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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: SCV001741205.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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Pathogenic
(Oct 05, 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: SCV002075345.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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Pathogenic
(Jun 18, 2024)
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no assertion criteria provided
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: SCV004110155.3
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
The IDUA c.1205G>A variant is predicted to result in premature protein termination (p.Trp402*). This variant has been repeatedly reported to be pathogenic for mucopolysaccharidosis type … (more)
The IDUA c.1205G>A variant is predicted to result in premature protein termination (p.Trp402*). This variant has been repeatedly reported to be pathogenic for mucopolysaccharidosis type I (Scott et al. 1992. PubMed ID: 1301196; Pollard et al. 2013. PubMed ID: 22976768; Ahmed et al. 2014. PubMed ID: 24368159; Bush et al. 2019. PubMed ID: PMID: 29654546; Cospain et al. 2020. PubMed ID: 32670797). This variant is reported in 0.14% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in IDUA gene are expected to be pathogenic. In summary, we classify this variant 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: SCV001973955.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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Mucopolysaccharidosis type 1
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000264385.3
First in ClinVar: Mar 05, 2016 Last updated: Oct 01, 2022 |
Comment:
Common pathogenic variant in persons of European ancestry and Australasia
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Comment:
Comment:
PVS1: nonsense. PP1: Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease. PM2: Very low frequency in GnomAD
Comment:
The p.Trp402X variant in IDUA has been reported in several individuals with muco polysaccharidosis type I (MPS-I) and has been associated with the severe Hurler syndrome phenotype in the homozygous state (Scott 1992, Pollard 2013, Cobos 2015 , Ahmed 2014, Oussoren 2013, Leroux 2014). It was absent form large population s tudies. This nonsense variant leads to a premature termination codon at positio n 402, which is predicted to lead to a truncated or absent protein. In mouse mod els, this variant led to phenotypes associated with the disease (Wang 2010). In summary, the p.Trp402X variant meets our criteria to be classified as pathogenic for mucopolysaccharidosis type I in an autosomal recessive manner, based upon i ts identification with patients, predicted functional impact and animal model st udies.
Comment:
NM_000203.3(IDUA):c.1205G>A(W402*) is classified as pathogenic in the context of mucopolysaccharidosis type I. Sources cited for classification include the following: PMID 1301196, 21394825, 7951228 and 11735025. Classification of NM_000203.3(IDUA):c.1205G>A(W402*) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Comment:
[ACMG/AMP: PVS1, PS3, PS4_Moderate, PP5] This alteration is a null variant in a gene where LOF is a known mechanism of disease [PVS1], is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3], has previously been observed in multiple unrelated patients with the same phenotype [PS4_Moderate], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5].
Comment:
The c.1205G>A (p.W402*) alteration, located in exon 9 (coding exon 9) of the IDUA gene, consists of a G to A substitution at nucleotide position 1205. This changes the amino acid from a tryptophan (W) to a stop codon at amino acid position 402. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration has been detected in the homozygous state, and in conjunction with a pathogenic IDUA mutation, in multiple individuals with mucopolysaccharidosis type I (MPS1) (Gort, 1998; Scott, 1992; Li, 2002; Bush, 2019; Guffon, 2021). Based on the available evidence, this alteration is classified as pathogenic.
Comment:
ACMG categories: PVS1,PM2,PP3,PP5
Comment:
The IDUA c.1205G>A (p.Trp402Ter) variant is a stop-gained variant and is well described in the literature as a pathogenic variant associated with mucopolysaccharidosis type I, accounting for 37% of disease alleles in Europeans, 43% in North Americans of European ancestry, and 55% of Australasians (Clarke et al. 2016). The p.Trp402Ter variant has been reported in at least seven studies in which it is found in a total of at least 30 individuals with mucopolysaccharidosis type I, including in 12 in a homozygous state, in at least 17 in a compound heterozygous state, and in one in a heterozygous state where a second variant was not identified. The variant was also found in an additional 93 of 298 disease alleles of unspecified zygosity (Scott et al. 1992; Beesley et al. 2001; Pollard et al. 2013; Oussoren et al. 2013; Ahmed et al. 2014; Leroux et al. 2014; Atceken et al. 2016). The p.Trp402Ter variant was absent from 20 control alleles but is reported at a frequency of 0.00045 in the combined European American and African American populations of the Exome Sequencing Project. Functional studies demonstrated that the variant resulted in low or undetectable IDUA activity in the homozygous state and 50% activity in the heterozygous state in human and mouse (Scott et al. 1992; Beesley et al. 2001; Wang et al. 2010; Oussoren et al. 2013; Leroux et al. 2014). Due to the potential impact of stop-gained variants and the supporting evidence, the p.Trp402Ter 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.
Comment:
The heterozygous p.Trp402Ter variant in IDUA was identified by our study in the compound heterozygous state, with another pathogenic variant, in one individual with Hurler-Scheie syndrome. This variant was absent from large population studies. This nonsense variant leads to a premature termination codon at position 402, 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. This variant has also been reported pathogenic in ClinVar (Variation ID: 11908) and is a well-known pathogenic variant in individuals with Hurler-Scheie syndrome that was reported in the homozygous and heterozygous state (86/200 alleles) of individuals with Hurler-Scheie syndrome from two cohorts (PMID: 22976768, 29393969, 11735025). 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).
Comment:
Variant summary: IDUA c.1205G>A (p.Trp402X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00059 in 90548 control chromosomes. c.1205G>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type 1 and is reported as one of the most common pathogenic variants causing Mucopolysaccharidosis type I. Clinical and functional data are consistent with the pathogenic outcome for the variant. 11 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
One of the most common pathogenic variants identified in European and American individuals with mucopolysaccharidosis type I, accounting for 17-48% of pathogenic variants in these populations (Bunge et al., 1994; Beesley et al., 2001; Pollard et al., 2013); 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: 32371413, 31980526, 32670797, 7951228, 30548430, 29654546, 1301196, 22976768, 26965916, 27511503, 15081804, 21364962, 8213840, 12509712, 8554071, 9427149, 11735025, 25525159, 19751987, 24368159, 23786846, 24698225, 30609409)
Comment:
The p.Trp402Ter variant in IDUA has been reported in at least 85 individuals with mucopolysaccharidosis (MSP) (PMID: 28752568, 10215409) and has been identified in 0.142% (69/48650) of European (non-Finnish) chromosomes, 0.046% (9/19442) of Latino chromosomes, and 0.034% (3/8772) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121965019). 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: 11908) as pathogenic by 12 submitters. Animal models in mice have shown that this variant causes MSP (doi: 10.1016/j.ymgme.2014.12.026). This nonsense variant leads to a premature termination codon at position 402, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the IDUA gene is an established disease mechanism in MSP. The phenotype of individuals compound heterozygous for this variant is highly specific for MSP based on very low alpha-L-iduronidase activity consistent with disease (PMID: 28752568). The presence of this variant in 38 affected homozygotes and in combination with reported pathogenic variants in at least 38 affected individuals increases the likelihood that the p.Trp402Ter variant is pathogenic (VariationID: 222996, 11909, 167190; PMID: 28752568, 10215409). In summary, this variant meets criteria to be classified as pathogenic for MSP in an autosomal recessive manner based on the prediction that it will cause loss of function, mouse models, and the presence of the variant in affected homozygotes. ACMG/AMP Criteria applied: PVS1, PM3_very-strong, PS3, PP4 (Richards 2015).
Comment:
PVS1, PS3, PP1, PM3
Comment:
ACMG classification criteria: PVS1, PM2_supporting, PM3, PP4
Comment:
This sequence change creates a premature translational stop signal (p.Trp402*) 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 (rs121965019, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individuals with mucopolysaccharidosis type I (PMID: 1301196, 11735025, 20301341, 21394825, 22976768). ClinVar contains an entry for this variant (Variation ID: 11908). For these reasons, this variant has been classified as Pathogenic.
Comment:
The IDUA c.1205G>A (p.Trp402Ter) variant is the most common reported variant in individuals affected with mucopolysaccharidosis I. This variant has been observed in both a homozygous and compound heterozygous state in affected individuals (Beesley CE et al., PMID: 11735025; Bertola F et al., PMID: 21394825; Gort L et al., PMID: 10215409; Pollard LM et al., PMID: 22976768; Scott HS et al., PMID: 1301196). This variant causes a stop gain, which is predicted to lead to nonsense mediated decay. In vivo mouse studies modeling this variant show no detectable alpha-L-iduronidase activity, indicating that this variant impacts protein function (Wang D et al., PMID: 19751987). The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 0.14% in the European non-Finnish population. This variant has been reported in the ClinVar database as a germline pathogenic variant by ten submitters. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.
Comment:
IDUA: PM3:Very Strong, PVS1, PM2
Comment:
The IDUA c.1205G>A variant is predicted to result in premature protein termination (p.Trp402*). This variant has been repeatedly reported to be pathogenic for mucopolysaccharidosis type I (Scott et al. 1992. PubMed ID: 1301196; Pollard et al. 2013. PubMed ID: 22976768; Ahmed et al. 2014. PubMed ID: 24368159; Bush et al. 2019. PubMed ID: PMID: 29654546; Cospain et al. 2020. PubMed ID: 32670797). This variant is reported in 0.14% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in IDUA gene are expected to be pathogenic. In summary, we classify this variant as pathogenic.
Comment:
Common pathogenic variant in persons of European ancestry and Australasia
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 c.1205G>A (p.Trp402ter) nonsense variant in the IDUA gene is the most common variant reported in individuals affected with Hurler Syndrome (Scott et al., 1992; Pollard et al., 2013; Leroux et al., 2014). The p.Trp402ter variant is predicted to cause a protein termination in exon 9 (out of a total of 14 exons in the coding sequence). Nonsense variants have been described in the IDUA gene in several affected individuals (Scott et al., 1992; Pollard et al., 2013) and are, therefore, a common mechanism of disease. Multiple in vivo functional studies have demonstrated the p.Trp402ter variant results in IDUA deficiency (Scott et al., 1992; Wang et al., 2009; Oussoren et al., 2013). This c.1205G>A variant has not been reported in the three population databases (Exome Sequencing Project [ESP], 1000 Genomes, and ExAC). Multiple in silico algorithms predict this variant to have a deleterious effect (GERP = 4.86; CADD = 41), and reputable diagnostic laboratories have reported this variant as pathogenic. IDUA is the only gene in which pathogenic variants are known to cause Hurler Syndrome. Therefore, this collective evidence supports the classification of the c.1205G>A (p.Trp402ter) as a Pathogenic variant for Hurler Syndrome.
Comment:
PVS1: nonsense. PP1: Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease. PM2: Very low frequency in GnomAD
Comment:
The p.Trp402X variant in IDUA has been reported in several individuals with muco polysaccharidosis type I (MPS-I) and has been associated with the severe Hurler syndrome phenotype in the homozygous state (Scott 1992, Pollard 2013, Cobos 2015 , Ahmed 2014, Oussoren 2013, Leroux 2014). It was absent form large population s tudies. This nonsense variant leads to a premature termination codon at positio n 402, which is predicted to lead to a truncated or absent protein. In mouse mod els, this variant led to phenotypes associated with the disease (Wang 2010). In summary, the p.Trp402X variant meets our criteria to be classified as pathogenic for mucopolysaccharidosis type I in an autosomal recessive manner, based upon i ts identification with patients, predicted functional impact and animal model st udies.
Comment:
NM_000203.3(IDUA):c.1205G>A(W402*) is classified as pathogenic in the context of mucopolysaccharidosis type I. Sources cited for classification include the following: PMID 1301196, 21394825, 7951228 and 11735025. Classification of NM_000203.3(IDUA):c.1205G>A(W402*) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Comment:
[ACMG/AMP: PVS1, PS3, PS4_Moderate, PP5] This alteration is a null variant in a gene where LOF is a known mechanism of disease [PVS1], is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3], has previously been observed in multiple unrelated patients with the same phenotype [PS4_Moderate], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5].
Comment:
The c.1205G>A (p.W402*) alteration, located in exon 9 (coding exon 9) of the IDUA gene, consists of a G to A substitution at nucleotide position 1205. This changes the amino acid from a tryptophan (W) to a stop codon at amino acid position 402. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration has been detected in the homozygous state, and in conjunction with a pathogenic IDUA mutation, in multiple individuals with mucopolysaccharidosis type I (MPS1) (Gort, 1998; Scott, 1992; Li, 2002; Bush, 2019; Guffon, 2021). Based on the available evidence, this alteration is classified as pathogenic.
Comment:
ACMG categories: PVS1,PM2,PP3,PP5
Comment:
The IDUA c.1205G>A (p.Trp402Ter) variant is a stop-gained variant and is well described in the literature as a pathogenic variant associated with mucopolysaccharidosis type I, accounting for 37% of disease alleles in Europeans, 43% in North Americans of European ancestry, and 55% of Australasians (Clarke et al. 2016). The p.Trp402Ter variant has been reported in at least seven studies in which it is found in a total of at least 30 individuals with mucopolysaccharidosis type I, including in 12 in a homozygous state, in at least 17 in a compound heterozygous state, and in one in a heterozygous state where a second variant was not identified. The variant was also found in an additional 93 of 298 disease alleles of unspecified zygosity (Scott et al. 1992; Beesley et al. 2001; Pollard et al. 2013; Oussoren et al. 2013; Ahmed et al. 2014; Leroux et al. 2014; Atceken et al. 2016). The p.Trp402Ter variant was absent from 20 control alleles but is reported at a frequency of 0.00045 in the combined European American and African American populations of the Exome Sequencing Project. Functional studies demonstrated that the variant resulted in low or undetectable IDUA activity in the homozygous state and 50% activity in the heterozygous state in human and mouse (Scott et al. 1992; Beesley et al. 2001; Wang et al. 2010; Oussoren et al. 2013; Leroux et al. 2014). Due to the potential impact of stop-gained variants and the supporting evidence, the p.Trp402Ter 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.
Comment:
The heterozygous p.Trp402Ter variant in IDUA was identified by our study in the compound heterozygous state, with another pathogenic variant, in one individual with Hurler-Scheie syndrome. This variant was absent from large population studies. This nonsense variant leads to a premature termination codon at position 402, 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. This variant has also been reported pathogenic in ClinVar (Variation ID: 11908) and is a well-known pathogenic variant in individuals with Hurler-Scheie syndrome that was reported in the homozygous and heterozygous state (86/200 alleles) of individuals with Hurler-Scheie syndrome from two cohorts (PMID: 22976768, 29393969, 11735025). 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).
Comment:
Variant summary: IDUA c.1205G>A (p.Trp402X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00059 in 90548 control chromosomes. c.1205G>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type 1 and is reported as one of the most common pathogenic variants causing Mucopolysaccharidosis type I. Clinical and functional data are consistent with the pathogenic outcome for the variant. 11 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
One of the most common pathogenic variants identified in European and American individuals with mucopolysaccharidosis type I, accounting for 17-48% of pathogenic variants in these populations (Bunge et al., 1994; Beesley et al., 2001; Pollard et al., 2013); 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: 32371413, 31980526, 32670797, 7951228, 30548430, 29654546, 1301196, 22976768, 26965916, 27511503, 15081804, 21364962, 8213840, 12509712, 8554071, 9427149, 11735025, 25525159, 19751987, 24368159, 23786846, 24698225, 30609409)
Comment:
The p.Trp402Ter variant in IDUA has been reported in at least 85 individuals with mucopolysaccharidosis (MSP) (PMID: 28752568, 10215409) and has been identified in 0.142% (69/48650) of European (non-Finnish) chromosomes, 0.046% (9/19442) of Latino chromosomes, and 0.034% (3/8772) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121965019). 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: 11908) as pathogenic by 12 submitters. Animal models in mice have shown that this variant causes MSP (doi: 10.1016/j.ymgme.2014.12.026). This nonsense variant leads to a premature termination codon at position 402, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the IDUA gene is an established disease mechanism in MSP. The phenotype of individuals compound heterozygous for this variant is highly specific for MSP based on very low alpha-L-iduronidase activity consistent with disease (PMID: 28752568). The presence of this variant in 38 affected homozygotes and in combination with reported pathogenic variants in at least 38 affected individuals increases the likelihood that the p.Trp402Ter variant is pathogenic (VariationID: 222996, 11909, 167190; PMID: 28752568, 10215409). In summary, this variant meets criteria to be classified as pathogenic for MSP in an autosomal recessive manner based on the prediction that it will cause loss of function, mouse models, and the presence of the variant in affected homozygotes. ACMG/AMP Criteria applied: PVS1, PM3_very-strong, PS3, PP4 (Richards 2015).
Comment:
PVS1, PS3, PP1, PM3
Comment:
ACMG classification criteria: PVS1, PM2_supporting, PM3, PP4
Comment:
This sequence change creates a premature translational stop signal (p.Trp402*) 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 (rs121965019, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individuals with mucopolysaccharidosis type I (PMID: 1301196, 11735025, 20301341, 21394825, 22976768). ClinVar contains an entry for this variant (Variation ID: 11908). For these reasons, this variant has been classified as Pathogenic.
Comment:
The IDUA c.1205G>A (p.Trp402Ter) variant is the most common reported variant in individuals affected with mucopolysaccharidosis I. This variant has been observed in both a homozygous and compound heterozygous state in affected individuals (Beesley CE et al., PMID: 11735025; Bertola F et al., PMID: 21394825; Gort L et al., PMID: 10215409; Pollard LM et al., PMID: 22976768; Scott HS et al., PMID: 1301196). This variant causes a stop gain, which is predicted to lead to nonsense mediated decay. In vivo mouse studies modeling this variant show no detectable alpha-L-iduronidase activity, indicating that this variant impacts protein function (Wang D et al., PMID: 19751987). The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 0.14% in the European non-Finnish population. This variant has been reported in the ClinVar database as a germline pathogenic variant by ten submitters. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.
Comment:
IDUA: PM3:Very Strong, PVS1, PM2
Comment:
The IDUA c.1205G>A variant is predicted to result in premature protein termination (p.Trp402*). This variant has been repeatedly reported to be pathogenic for mucopolysaccharidosis type I (Scott et al. 1992. PubMed ID: 1301196; Pollard et al. 2013. PubMed ID: 22976768; Ahmed et al. 2014. PubMed ID: 24368159; Bush et al. 2019. PubMed ID: PMID: 29654546; Cospain et al. 2020. PubMed ID: 32670797). This variant is reported in 0.14% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in IDUA gene are expected to be pathogenic. In summary, we classify this variant as pathogenic.
Comment:
Common pathogenic variant in persons of European ancestry and Australasia
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Mucopolysaccharidosis Type I. | Adam MP | - | 2024 | PMID: 20301341 |
| Long term disease burden post-transplantation: three decades of observations in 25 Hurler patients successfully treated with hematopoietic stem cell transplantation (HSCT). | Guffon N | Orphanet journal of rare diseases | 2021 | PMID: 33517895 |
| Neonatal Onset Interstitial Lung Disease as a Primary Presenting Manifestation of Mucopolysaccharidosis Type I. | Bush D | JIMD reports | 2019 | PMID: 29654546 |
| 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 |
| Evaluation and identification of IDUA gene mutations in Turkishpatients with mucopolysaccharidosis type I. | Atçeken N | Turkish journal of medical sciences | 2016 | PMID: 27511503 |
| Dried blood spots allow targeted screening to diagnose mucopolysaccharidosis and mucolipidosis. | Cobos PN | JIMD reports | 2015 | PMID: 24798265 |
| [Hurler syndrome: early diagnosis and treatment]. | Leroux S | Archives de pediatrie : organe officiel de la Societe francaise de pediatrie | 2014 | PMID: 24698225 |
| 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 |
| 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 |
| 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 |
| Characterization of an MPS I-H knock-in mouse that carries a nonsense mutation analogous to the human IDUA-W402X mutation. | Wang D | Molecular genetics and metabolism | 2010 | PMID: 19751987 |
| Diversity of mutations and distribution of single nucleotide polymorphic alleles in the human alpha-L-iduronidase (IDUA) gene. | Li P | Genetics in medicine : official journal of the American College of Medical Genetics | 2002 | PMID: 12509712 |
| 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 |
| 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: diagnostic, clinical, and biological implications. | Scott HS | Human mutation | 1995 | PMID: 8680403 |
| 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 |
| A common mutation for mucopolysaccharidosis type I associated with a severe Hurler syndrome phenotype. | Scott HS | Human mutation | 1992 | PMID: 1301196 |
| The genetic mucopolysaccharidoses. | McKusick VA | Medicine | 1965 | PMID: 4221470 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=IDUA | - | - | - | - |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/1d63007e-b100-4d67-a87b-8ec17b0a831e | - | - | - | - |
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Text-mined citations for rs121965019 ...
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Record last updated Nov 03, 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.