ClinVar Miner

Submissions for variant NM_000203.5(IDUA):c.1045G>A (p.Asp349Asn) (rs368454909)

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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 RCV000180110 SCV000232486 pathogenic not provided 2012-11-30 criteria provided, single submitter clinical testing
Invitae RCV001248916 SCV001576109 likely pathogenic Mucopolysaccharidosis type 1 2020-05-20 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 349 of the IDUA protein (p.Asp349Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs368454909, ExAC 0.01%). This variant has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 8680403, 31194252). ClinVar contains an entry for this variant (Variation ID: 92623). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). This variant disrupts the p.Asp349 amino acid residue in IDUA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12203999, 12559846). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Broad Institute Rare Disease Group, Broad Institute RCV001248916 SCV001422672 likely pathogenic Mucopolysaccharidosis type 1 2020-01-14 no assertion criteria provided curation The p.Asp349Asn variant in IDUA has been reported in 2 individuals with mucopolysaccharidosis (MPS) (PMID: 1627351, 8680403) and has been identified in 0.006% (1/15972) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs368454909). 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: 92623) as pathogenic by EGL Genetic Diagnostics. In vitro functional studies provide some evidence that the p.Asp349Asn variant may impact protein function (PMID: 1627351). 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 a reported pathogenic variant in an individual with MPS increases the likelihood that the p.Asp349Asn variant is pathogenic (VariationID: 11909; PMID: 8680403). This variant is located in a region of IDUA that is essential to substrate binding, suggesting that this variant is in a functional domain and supports pathogenicity (PMID: 24036510, 23959878, 1627351). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM1, PS3_moderate, PP3, PM3_supporting (Richards 2015).

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