rs772416503
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000203.5(IDUA):c.1487C>G(p.Pro496Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000265 in 1,511,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P496L) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000203.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IDUA | NM_000203.5 | c.1487C>G | p.Pro496Arg | missense_variant | 10/14 | ENST00000514224.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IDUA | ENST00000514224.2 | c.1487C>G | p.Pro496Arg | missense_variant | 10/14 | 2 | NM_000203.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151960Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000139 AC: 2AN: 143870Hom.: 0 AF XY: 0.0000241 AC XY: 2AN XY: 82914
GnomAD4 exome AF: 0.00000221 AC: 3AN: 1359134Hom.: 0 Cov.: 37 AF XY: 0.00000148 AC XY: 1AN XY: 674164
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 151960Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74216
ClinVar
Submissions by phenotype
Mucopolysaccharidosis type 1 Pathogenic:5
Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 13, 2020 | The p.Pro496Arg variant in IDUA has been reported in at least 13 individuals with mucopolysaccharidosis (MPS) (PMID: 21394825, 28752568, 27520059) and has been identified in 0.003% (2/66872) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs772416503). 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: 496861) as pathogenic by Counsyl, EGL Genetic Diagnostics, and Integrated Genetics. In vitro functional studies provide some evidence that the p.Pro496Arg variant may impact protein function (PMID: 11735025). 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 presence of this variant in combination with reported pathogenic variants and in at least 8 individuals with MPS increases the likelihood that the p.Pro496Arg variant is pathogenic (VariationID: 193061, 11909, 11908; PMID: 21394825, 28752568). One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Pro496Leu, has been reported in association with disease in the literature and ClinVar, slightly supporting that a change at this position may not be tolerated (PMID: 7550232; Variation ID: 551675). In summary, this variant meets criteria to be classified as pathogenic for MPS in an autosomal recessive manner based on its presence in combination with other pathogenic variants in individuals with MPS and functional studies. ACMG/AMP Criteria applied: PM3_very-strong, PM2, PS3_moderate, PP3 (Richards 2015). - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 496 of the IDUA protein (p.Pro496Arg). This variant is present in population databases (rs772416503, gnomAD 0.003%). This missense change has been observed in individual(s) with Hurler syndrome (PMID: 21394825, 27520059). ClinVar contains an entry for this variant (Variation ID: 496861). 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: 11735025). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 24, 2018 | Variant summary: IDUA c.1487C>G (p.Pro496Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was observed with an allele frequency of 1.4e-05 in 145584 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in IDUA causing Mucopolysaccharidosis Type 1 (1.4e-05 vs 0.0027), allowing no conclusion about variant significance. The variant, c.1487C>G, has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type 1 (Beesley_2001, Bertola_2011). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "pathogenic."Based on the evidence outlined above, the variant was classified as pathogenic. - |
Likely pathogenic, criteria provided, single submitter | literature only | Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova | Jan 01, 2019 | PS3: Low in vitro enzymatic activity. PM2: Very low frequency in ExAC. PP3: Multiple lines of computational evidence supporting a deleterious effect - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 15, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 30, 2017 | - - |
Hurler syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 21, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at