ClinVar Miner

Submissions for variant NM_000203.5(IDUA):c.1598C>T (p.Pro533Leu) (rs121965021)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000493029 SCV000700467 likely pathogenic not provided 2017-05-08 criteria provided, single submitter clinical testing
GeneDx RCV000493029 SCV000581710 not provided not provided no assertion provided clinical testing The P533R variant in the IDUA gene has been reported previously in the homozygous state or in the heterozygous state with a presumed second IDUA variant in individuals with MPS I (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 the heterozygous state with a second IDUA variant in two individuals with MPS I (Voskoboeva et al., 1998). Therefore, we interpret P533R as a pathogenic variant.
Broad Institute Rare Disease Group, Broad Institute RCV001249043 SCV001422983 likely pathogenic Mucopolysaccharidosis type 1 2020-01-13 no assertion criteria provided curation The p.Pro533Leu variant in IDUA has been reported in 4 individuals with mucopolysaccharidosis (MPS) (PMID: 9787109, 27511503; doi: 10.7124/bc.00093B) and was absent from large population studies and no high quality genotypes at this site were noted to include this variant. This variant has also been reported in ClinVar (VariationID: 429205) as likely pathogenic by EGL Genetic Diagnostics. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional pathogenic variant, resulting in a different amino acid change at the same position, p.Pro533Arg, has been reported in association with disease in the literature and ClinVar, supporting that a change at this position may not be tolerated (VariationID: 11910; PMID: 24036510, 28752568, 27196898, 19748810). The p.Pro533Leu 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: 24480078, 9787109, 27511503). The presence of this variant in one affected homozygote and in combination with a reported pathogenic variant in 2 individuals with MPS increases the likelihood that the p.Pro533Leu variant is pathogenic (VariationID: 11909; PMID: 9787109, 27511503; doi: 10.7124/bc.00093B). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM5, PM3, PM1, PM2_supporting, PP3 (Richards 2015).

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