4-1003418-C-G
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS3_SupportingPP1_ModeratePP4_ModeratePM2_SupportingPM3PP3_Moderate
This summary comes from the ClinGen Evidence Repository: The NM_000203.5:c.1598C>G variant in IDUA is a missense variant that is predicted to result in the substitution of proline by arginine at amino acid 533 (p.Pro533Arg). This variant is one of the more common variants identified in patients with mucopolysaccharidosis type 1 (MPS 1). The variant was found in 46 out of 538 patients in the International MPS 1 Registry (PMID:31194252). It has been identified in patients with MPS 1 from different continents, and it is the most frequent variant in the north African countries (92% of MPS1 alleles in Morocco, 81% in Algeria, and 54% in Tunisia) (reviewed in PMID:29393969). Of note, the severity of symptoms in individuals with this variant is variable; some homozygous individuals have severe disease while others have attenuated symptoms (PMID:31194252). At least 50 patients with this variant have been reported including patients with documented laboratory values showing deficient iduronidase activity and detailed features consistent with MPS 1 such as dysmorphic facies, multiple dysostoses, joint stiffness, hepatomegaly, umbilical hernia, hearing loss, cardiovascular disease, and hydrocephalus and/or elevated urine GAGs (2 PP4 criteria met) (PMID:10738517, 12796790, 1301941). One study provides details on the clinical features, IDUA activity, and GAG values for 9 patients (3 PP4 criteria met, PMID:27196898) (PP4_Moderate). At least 24 individuals are homozygous for the variant (PMID:1301941, 10738517, 12203999, 16435195, 24102521, 27196898, 28752568, 31194252, 31298590). At least 12 individuals are compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, including at least 8 patients with c.1205G>A (p.Trp402Ter) (ClinVar Variation ID: 11908) (max 2 x 0.5 points), two patients with c.208C>T (p.Gln70Ter) (PMID:31194252) (ClinVar Variation ID: 11909) (2 x 0.5 points), two apparently unrelated patients with c.1743C>G (p.Tyr581Ter) (ClinVar Variation ID: 550883) (2 x 0.5 points), and at least 24 homozygotes (max 2 x 0.5 points) (PMID:31194252). 4 PM3 points (PM3_VeryStrong). Many additional individuals have been reported who are compound heterozygous for additional IDUA variants (PMID:12203999, 12559846, 31194252). Additional evidence is available in the literature but the maximum points for PM3 have been reached (PM3_Very Strong). The variant has been shown to segregate with disease in families, including two families each with two affected children who are homozygous for the variant (PMID:27196898) (PP1_Moderate). The highest population minor allele frequency in gnomAD v4.1.0. is 0.0001975 (10/50624 alleles) in the Admixed American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). Expression of the variant in CHO cells and tobacco BY-2 cells revealed that the protein is unstable, abnormally processed/trafficked, and has very low, but detectable (<1%), residual activity when compared to wild type (PMID:12559846, 24036510) (PS3_Supporting). The computational predictor REVEL gives a score of 0.783 which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level (PP3_Moderate). No impact on splicing predicted by SpliceAI. There is a ClinVar entry for this variant (Variant ID: 11910). In summary, this variant meets the criteria to be classified as pathogenic for MPS 1. IDUA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases VCEP: PM3_Very Strong, PP1_Moderate, PP3_Moderate, PP4_Moderate, PS3_Supporting, PM2_Supporting.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on January 3, 2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA256112/MONDO:0001586/091
Frequency
Consequence
NM_000203.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.0000263 AC: 4AN: 152106Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000555 AC: 7AN: 126026Hom.: 0 AF XY: 0.0000289 AC XY: 2AN XY: 69148
GnomAD4 exome AF: 0.0000298 AC: 41AN: 1376970Hom.: 0 Cov.: 33 AF XY: 0.0000353 AC XY: 24AN XY: 679424
GnomAD4 genome 0.0000263 AC: 4AN: 152106Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74310
ClinVar
Submissions by phenotype
Mucopolysaccharidosis type 1 Pathogenic:5Other:1
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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -
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). -
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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. -
Common pathogenic variant in Italy -
The NM_000203.5:c.1598C>G variant in IDUA is a missense variant that is predicted to result in the substitution of proline by arginine at amino acid 533 (p.Pro533Arg). This variant is one of the more common variants identified in patients with mucopolysaccharidosis type 1 (MPS 1). The variant was found in 46 out of 538 patients in the International MPS 1 Registry (PMID: 31194252). It has been identified in patients with MPS 1 from different continents, and it is the most frequent variant in the north African countries (92% of MPS1 alleles in Morocco, 81% in Algeria, and 54% in Tunisia) (reviewed in PMID: 29393969). Of note, the severity of symptoms in individuals with this variant is variable; some homozygous individuals have severe disease while others have attenuated symptoms (PMID: 31194252). At least 50 patients with this variant have been reported including patients with documented laboratory values showing deficient iduronidase activity and detailed features consistent with MPS 1 such as dysmorphic facies, multiple dysostoses, joint stiffness, hepatomegaly, umbilical hernia, hearing loss, cardiovascular disease, and hydrocephalus and/or elevated urine GAGs (2 PP4 criteria met) (PMID: 10738517, 12796790, 1301941). One study provides details on the clinical features, IDUA activity, and GAG values for 9 patients (3 PP4 criteria met, PMID: 27196898) (PP4_Moderate). At least 24 individuals are homozygous for the variant (PMID: 1301941, 10738517, 12203999, 16435195, 24102521, 27196898, 28752568, 31194252, 31298590). At least 12 individuals are compound heterozygous for the variant and another variant in IDUA that has been classified as pathogenic by the ClinGen Lysosomal Diseases VCEP, including at least 8 patients with c.1205G>A (p.Trp402Ter) (ClinVar Variation ID: 11908) (max 2 x 0.5 points), two patients with c.208C>T (p.Gln70Ter) (PMID: 31194252) (ClinVar Variation ID: 11909) (2 x 0.5 points), two apparently unrelated patients with c.1743C>G (p.Tyr581Ter) (ClinVar Variation ID: 550883) (2 x 0.5 points), and at least 24 homozygotes (max 2 x 0.5 points) (PMID: 31194252). 4 PM3 points (PM3_VeryStrong). Many additional individuals have been reported who are compound heterozygous for additional IDUA variants (PMID: 12203999, 12559846, 31194252). Additional evidence is available in the literature but the maximum points for PM3 have been reached (PM3_Very Strong). The variant has been shown to segregate with disease in families, including two families each with two affected children who are homozygous for the variant (PMID: 27196898) (PP1_Moderate). The highest population minor allele frequency in gnomAD v4.1.0. is 0.0001975 (10/50624 alleles) in the Admixed American population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.00025), meeting this criterion (PM2_Supporting). Expression of the variant in CHO cells and tobacco BY-2 cells revealed that the protein is unstable, abnormally processed/trafficked, and has very low, but detectable (<1%), residual activity when compared to wild type (PMID: 12559846, 24036510) (PS3_Supporting). The computational predictor REVEL gives a score of 0.783 which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level (PP3_Moderate). No impact on splicing predicted by SpliceAI. There is a ClinVar entry for this variant (Variant ID: 11910). In summary, this variant meets the criteria to be classified as pathogenic for MPS 1. IDUA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases VCEP: PM3_Very Strong, PP1_Moderate, PP3_Moderate, PP4_Moderate, PS3_Supporting, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on January 3, 2025) -
not provided Pathogenic:5
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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. -
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Hurler syndrome Pathogenic:3
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
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Inborn genetic diseases Pathogenic:1
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. -
Mucopolysaccharidosis, MPS-I-S Pathogenic:1
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]. -
Mucopolysaccharidosis, MPS-I-S;C0086431:Mucopolysaccharidosis, MPS-I-H/S;C0086795:Hurler syndrome Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at