rs121965019
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000203.5(IDUA):c.1205G>A(p.Trp402Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00127 in 1,485,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.00086 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0013 ( 0 hom. )
Consequence
IDUA
NM_000203.5 stop_gained
NM_000203.5 stop_gained
Scores
4
1
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Clinical Significance
Conservation
PhyloP100: 0.133
Genes affected
IDUA (HGNC:5391): (alpha-L-iduronidase) This gene encodes an enzyme that hydrolyzes the terminal alpha-L-iduronic acid residues of two glycosaminoglycans, dermatan sulfate and heparan sulfate. This hydrolysis is required for the lysosomal degradation of these glycosaminoglycans. Mutations in this gene that result in enzymatic deficiency lead to the autosomal recessive disease mucopolysaccharidosis type I (MPS I). [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 4-1002747-G-A is Pathogenic according to our data. Variant chr4-1002747-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 11908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-1002747-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| IDUA | NM_000203.5 | c.1205G>A | p.Trp402Ter | stop_gained | 9/14 | ENST00000514224.2 | NP_000194.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| IDUA | ENST00000514224.2 | c.1205G>A | p.Trp402Ter | stop_gained | 9/14 | 2 | NM_000203.5 | ENSP00000425081 | P1 |
Frequencies
GnomAD3 genomes 0.000860 AC: 130AN: 151238Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000585 AC: 53AN: 90548Hom.: 0 AF XY: 0.000489 AC XY: 25AN XY: 51134
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GnomAD4 exome AF: 0.00131 AC: 1750AN: 1334448Hom.: 0 Cov.: 34 AF XY: 0.00130 AC XY: 852AN XY: 657900
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GnomAD4 genome 0.000859 AC: 130AN: 151342Hom.: 0 Cov.: 33 AF XY: 0.000744 AC XY: 55AN XY: 73930
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:29Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:8
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 11, 2020 | 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) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 12, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 31, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2024 | IDUA: PM3:Very Strong, PVS1, PM2 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 13, 2021 | - - |
Mucopolysaccharidosis type 1 Pathogenic:7Other:1
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 05, 2020 | - - |
| Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 13, 2020 | 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). - |
| not provided, no classification provided | literature only | GeneReviews | - | Common pathogenic variant in persons of European ancestry and Australasia - |
| Pathogenic, criteria provided, single submitter | literature only | Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova | Jan 01, 2019 | 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 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Oct 23, 2017 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 16, 2016 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 17, 2019 | 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. - |
Hurler syndrome Pathogenic:4
| Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2001 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Jan 27, 2016 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genomics Laboratory, Washington University in St. Louis | Feb 13, 2024 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 12, 2019 | 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. - |
Mucopolysaccharidosis, MPS-I-S;C0086431:Mucopolysaccharidosis, MPS-I-H/S;C0086795:Hurler syndrome Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital | Sep 15, 2017 | [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]. - |
| Pathogenic, no assertion criteria provided | research | Division of Human Genetics, Children's Hospital of Philadelphia | May 14, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Dec 29, 2021 | PVS1, PS3, PP1, PM3 - |
Mucopolysaccharidosis, MPS-I-H/S Pathogenic:2
| Pathogenic, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Dec 03, 2018 | 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). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Jul 08, 2016 | - - |
See cases Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital Muenster | Jul 04, 2023 | ACMG categories: PVS1,PM2,PP3,PP5 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Jan 03, 2024 | ACMG classification criteria: PVS1, PM2_supporting, PM3, PP4 - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 29, 2022 | 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. - |
IDUA-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 18, 2024 | 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. - |
Computational scores
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Name
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BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
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Pathogenic
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Pathogenic
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Pathogenic
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Benign
D
MutationTaster
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A;A;A
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at