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

gnomAD frequency: 0.00003  dbSNP: rs121965021

Total submissions: 16

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.
Eurofins Ntd Llc (ga)	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	2022-03-16	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000208595	SCV000933163	pathogenic	Mucopolysaccharidosis type 1	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 533 of the IDUA protein (p.Pro533Arg). This variant is present in population databases (rs121965021, gnomAD 0.02%). This missense change has been observed in individuals with mucopolysaccharidosis (PMID: 1301941, 10911525, 16435195, 21521498, 23786846, 24368159). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11910). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt IDUA protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects IDUA function (PMID: 24036510). For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000208595	SCV001422984	pathogenic	Mucopolysaccharidosis type 1	2020-01-14	criteria provided, single submitter	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, http://gnomad.broadinstitute.org; 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).
Ambry Genetics	RCV001267070	SCV001445251	pathogenic	Inborn genetic diseases	2022-03-31	criteria provided, single submitter	clinical testing	The c.1598C>G (p.P533R) alteration is located in coding exon 11 of the IDUA gene. This alteration results from a C to G substitution at nucleotide position 1598, causing the proline (P) at amino acid position 533 to be replaced by an arginine (R). Based on data from gnomAD, the G allele has an overall frequency of 0.01% (8/157288) total alleles studied. The highest observed frequency was 0.02% (1/4962) of Other alleles. This alteration has been reported in the homozygous or compound heterozygous state in individuals with mucopolysaccharidosis type I (Scott, 1992; Laradi, 2005; Fahiminiya, 2014; Ghosh, 2017; Clarke, 2019). Patients have presented with both the attenuated and severe phenotypes (Scott, 1992; Laradi, 2005; Clarke, 2019). This variant occurs with high frequency in the Moroccan, Sicilian, and Brazilian populations (reviewed in Matte, 2003). This amino acid position is highly conserved in available vertebrate species. Functional analysis has demonstrated that the p.P533R variant significantly decreases protein activity as compared to wild type protein. Fibroblast cells lines from a patient with this alteration and a second nonsense alteration had 0.5% of normal activity, while two homozygous patients had leukocyte protein activity at 1.2% of normal (Scott, 1992; Laradi, 2005). When expressed in CHO-K1 cells, this variant produced a small amount of protein that did not appear to undergo normal processing and had 0.04% of normal protein activity (Matte, 2003). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
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].
Revvity Omics, Revvity	RCV000486848	SCV002023123	pathogenic	not provided	2023-04-27	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV004595880	SCV005088825	pathogenic	Mucopolysaccharidosis, MPS-I-S	2020-04-11	criteria provided, single submitter	clinical testing	This variant was previously reported in patients diagnosed with mucopolysaccharidosis type I of different ethnicity in homozygous or compound heterozygote state [PMID: 1301941, 10911525, 21521498, 24368159, 16435195, 23786846] and reported to segregate with mucopolysaccharidosis in two families [PMID: 21521498]. Functional analysis of the variant suggested that this variant leads to a 50% reduction in the enzymatic activity of IDUA protein and confers lower thermodynamic stability compared to wild type protein [PMID: 24036510].
OMIM	RCV000012685	SCV000032920	pathogenic	Hurler syndrome	1999-01-01	no assertion criteria provided	literature only
GeneReviews	RCV000208595	SCV000264386	not provided	Mucopolysaccharidosis type 1		no assertion provided	literature only	Common pathogenic variant in Italy
Counsyl	RCV000012685	SCV001132229	pathogenic	Hurler syndrome	2016-12-09	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000486848	SCV001952782	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000486848	SCV001969420	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000208595	SCV002075377	pathogenic	Mucopolysaccharidosis type 1	2020-07-28	no assertion criteria provided	clinical testing