ClinVar Miner

Submissions for variant NM_000203.5(IDUA):c.1205G>A (p.Trp402Ter) (rs121965019)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078374 SCV000232926 pathogenic not provided 2016-03-31 criteria provided, single submitter clinical testing
GeneDx RCV000078374 SCV000329822 pathogenic not provided 2018-06-18 criteria provided, single submitter clinical testing The W402X variant is one of the most common pathogenic variants identified in the IDUA gene and has been reported in several unrelated individuals with MPSI who were homozygous for W402X or heterozygous for W402X and a second pathogenic variant in the IDUA gene (Scott et al., 1992 ; Bunge et al., 1994; Beesley et al., 2001; Prommajan et al., 2011; Oussoren et al., 2013). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay and functional studies of the W402X variant indicate that it causes a significant reduction or complete loss of enzyme activity (Beesley et al., 2001; Prommajan et al., 2011). In summary, we interpret W402X to be a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000384297 SCV000451787 pathogenic Mucopolysaccharidosis type 1 2017-10-23 criteria provided, single submitter clinical testing 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.
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000012683 SCV000538044 pathogenic Hurler syndrome 2016-01-27 criteria provided, single submitter clinical testing 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.
Invitae RCV000384297 SCV000627147 pathogenic Mucopolysaccharidosis type 1 2020-01-07 criteria provided, single submitter clinical testing 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. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in multiple individuals affected with mucopolysaccharidosis type I (PMID: 1301196, 22976768, 21394825, 11735025, 20301341). ClinVar contains an entry for this variant (Variation ID: 11908). Loss-of-function variants in IDUA are known to be pathogenic (PMID: 21480867, 11735025). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000384297 SCV000695969 pathogenic Mucopolysaccharidosis type 1 2019-12-17 criteria provided, single submitter clinical testing 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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000384297 SCV000712125 pathogenic Mucopolysaccharidosis type 1 2016-05-16 criteria provided, single submitter clinical testing 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.
Fulgent Genetics,Fulgent Genetics RCV000477890 SCV000894345 pathogenic Mucopolysaccharidosis, MPS-I-S; Hurler syndrome; Mucopolysaccharidosis, MPS-I-H/S 2018-10-31 criteria provided, single submitter clinical testing
Laboratory of Diagnosis and Therapy of Lysosomal Disorders,University of Padova RCV000384297 SCV000929875 pathogenic Mucopolysaccharidosis type 1 2019-01-01 criteria provided, single submitter literature only 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
Broad Institute Rare Disease Group,Broad Institute RCV001004934 SCV001164454 pathogenic Mucopolysaccharidosis, MPS-I-H/S 2018-12-03 criteria provided, single submitter research 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).
Myriad Women's Health, Inc. RCV000012683 SCV001193947 pathogenic Hurler syndrome 2019-11-12 criteria provided, single submitter clinical testing 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.
Institute for Genomic Medicine (IGM) Clinical Laboratory,Nationwide Children's Hospital RCV000477890 SCV001423593 pathogenic Mucopolysaccharidosis, MPS-I-S; Hurler syndrome; Mucopolysaccharidosis, MPS-I-H/S 2017-09-15 criteria provided, single submitter clinical testing [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].
OMIM RCV000012683 SCV000032918 pathogenic Hurler syndrome 2001-11-01 no assertion criteria provided literature only
GeneReviews RCV000384297 SCV000264385 pathogenic Mucopolysaccharidosis type 1 2016-02-11 no assertion criteria provided literature only
Division of Human Genetics,Children's Hospital of Philadelphia RCV000477890 SCV000536710 pathogenic Mucopolysaccharidosis, MPS-I-S; Hurler syndrome; Mucopolysaccharidosis, MPS-I-H/S 2015-05-14 no assertion criteria provided research
Broad Institute Rare Disease Group,Broad Institute RCV000384297 SCV001422680 pathogenic Mucopolysaccharidosis type 1 2020-01-13 no assertion criteria provided curation 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).

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