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

gnomAD frequency: 0.00001  dbSNP: rs368454909

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000180110	SCV000232486	pathogenic	not provided	2012-11-30	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248916	SCV001422672	likely pathogenic	Mucopolysaccharidosis type 1	2020-01-14	criteria provided, single submitter	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).
Invitae	RCV001248916	SCV001576109	pathogenic	Mucopolysaccharidosis type 1	2023-04-22	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. 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. ClinVar contains an entry for this variant (Variation ID: 92623). This missense change has been observed in individuals with mucopolysaccharidosis type I (PMID: 8680403, 31194252). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 349 of the IDUA protein (p.Asp349Asn).
Revvity Omics, Revvity	RCV000180110	SCV002016683	likely pathogenic	not provided	2023-12-18	criteria provided, single submitter	clinical testing