ClinVar Miner

Submissions for variant NM_000203.5(IDUA):c.1598C>G (p.Pro533Arg) (rs121965021)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486848 SCV000568512 pathogenic not provided 2016-09-28 criteria provided, single submitter clinical testing The P533R variant in the IDUA gene has been reported previously in individuals with MPS I in the homozygous state or in the heterozygous state with a presumed second IDUA variant (Alif et al., 1999; Laradi et al., 2005; Fahiminiya et al., 2014). The P533R variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P533R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Functional studies of P533R indicate that this variant leads to a 50% reduction in the enzymatic rate of IDUA and confers lower thermodynamic stability compared to wild type protein (Bie et al., 2013). A missense variant in the same residue, P533L, has been previously identified in patients with MPS I in the homozygous state and in the heterozygous state with a second IDUA variant (Voskoboeva et al., 1998; Atceken et al., 2016). Therefore, we interpret P533R as a pathogenic variant.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000486848 SCV000700446 pathogenic not provided 2017-05-08 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763533 SCV000894346 pathogenic Mucopolysaccharidosis, MPS-I-S; Hurler syndrome; Mucopolysaccharidosis, MPS-I-H/S 2018-10-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000208595 SCV000919533 pathogenic Mucopolysaccharidosis type 1 2017-12-15 criteria provided, single submitter clinical testing Variant summary: The IDUA c.1598C>G (p.Pro533Arg) variant involves the alteration of a conserved nucleotide. 3/3 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 8/152678 control chromosomes at a frequency of 0.0000524, which does not exceed the estimated maximal expected allele frequency of a pathogenic IDUA variant (0.0026926). The variant was reported in numerous affected individuals in the literature in both the homozygous and compound heterozygous state. Homozygous patients have been reported to have undetectable IDUA activity (Chkioua_2011). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000208595 SCV000933163 pathogenic Mucopolysaccharidosis type 1 2020-09-24 criteria provided, single submitter clinical testing This sequence change replaces proline with arginine at codon 533 of the IDUA protein (p.Pro533Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. 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 observed to segregate with mucopolysaccharidosis in two families (PMID: 21521498) and it has been observed to be homozygous or in combination with another IDUA variant in individuals affected with condition (PMID: 1301941, 10911525, 21521498, 24368159, 16435195, 23786846). ClinVar contains an entry for this variant (Variation ID: 11910). Experimental studies have shown that this missense change abrogates enzyme activity, reduces substrate affinity and reduces thermal stability (PMID: 24036510). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV001267070 SCV001445251 pathogenic Inborn genetic diseases 2018-03-12 criteria provided, single submitter clinical testing
Baylor Genetics RCV000012685 SCV001520420 pathogenic Hurler syndrome 2019-07-03 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
OMIM RCV000012685 SCV000032920 pathogenic Hurler syndrome 1999-01-01 no assertion criteria provided literature only
GeneReviews RCV000208595 SCV000264386 pathogenic Mucopolysaccharidosis type 1 2016-02-11 no assertion criteria provided literature only
Counsyl RCV000012685 SCV001132229 pathogenic Hurler syndrome 2016-12-09 no assertion criteria provided clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000208595 SCV001422984 pathogenic Mucopolysaccharidosis type 1 2020-01-14 no assertion criteria provided curation The p.Pro533Arg variant in IDUA has been reported in at least 15 individuals with mucopolysaccharidosis (MPS), segregated with disease in 6 affected relatives from 3 families (PMID: 19748810, 27196898, 28752568) and has been Identified in 0.012% (3/24988) of Latino chromosomes and 0.006% (4/62590) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP rs121965021). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (VariationID: 11910) as pathogenic by GeneDx, EGL Genetic Diagnostics, Fulgent Genetics, OMIM, Integrated Genetics, and GeneReviews. In vitro functional studies provide some evidence that the p.Pro533Arg variant may slightly impact protein function (PMID: 24036510). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Pro533Arg variant is located in a region of IDUA that is essential to protein folding and stability, suggesting that this variant is in a functional domain and supports pathogenicity (PMID: 24036510). The phenotype of individuals homozygous and compound heterozygous for this variant is highly specific for MPS1 based on alpha-L-iduronidase levels being <1% of normal consistent with disease (PMID: 27196898). Additionally, the presence of this variant in at least 18 affected homozygotes and in combination with reported pathogenic variants in 2 individuals with MPS increases the likelihood that the p.Pro533Arg variant is pathogenic (VariationID: 11908, 280976; PMID: 19748810, 27196898, 28752568). In summary, this variant meets criteria to be classified as pathogenic for MPS1 in an autosomal recessive manner based on the presence of the variant in affected homozygotes and compound heterozygotes, co-segregation with disease, and the deleterious effect of the variant on protein folding and function. ACMG/AMP Criteria applied: PM3_strong, PP1_moderate, PM1, PM2_supporting, PP3, PP4, PS3_supporting (Richards 2015).
Human Genetics - Radboudumc,Radboudumc RCV000486848 SCV001952782 likely pathogenic not provided no assertion criteria provided clinical testing

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