ClinVar Miner

Submissions for variant NM_000203.5(IDUA):c.590-7G>A (rs762411583)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000669065 SCV000793766 pathogenic Hurler syndrome 2017-08-30 criteria provided, single submitter clinical testing
Invitae RCV000208601 SCV001232833 pathogenic Mucopolysaccharidosis type 1 2020-10-19 criteria provided, single submitter clinical testing This sequence change falls in intron 5 of the IDUA gene. It does not directly change the encoded amino acid sequence of the IDUA protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs762411583, ExAC 0.002%). This variant has been observed in individuals affected with Scheie syndrome (PMID: 8213840, 28752568). This variant is also known as 678-7G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 222996). Studies have shown that this variant is associated with activation of a cryptic splice acceptor, which introduces a frameshift (PMID:8318992). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000012688 SCV000032923 pathogenic Mucopolysaccharidosis, MPS-I-S 1993-11-01 no assertion criteria provided literature only
GeneReviews RCV000208601 SCV000264381 pathogenic Mucopolysaccharidosis type 1 2016-02-11 no assertion criteria provided literature only
Broad Institute Rare Disease Group, Broad Institute RCV000208601 SCV001422678 pathogenic Mucopolysaccharidosis type 1 2020-01-14 no assertion criteria provided curation The c.590-7G>A variant in IDUA has been reported in at least 10 individuals with mucopolysaccharidosis (MPS) (PMID: 28752568, 8213840, 9748610) and has been identified in 0.001% (1/106874) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP rs762411583). 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: 222996) as pathogenic by Counsyl, OMIM, and GeneReviews. Functional studies demonstrating that the variant activates a cryptic splice site provide some evidence that the c.590-7G>A variant may slightly impact protein function (PMID: 8213840). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant is located in the 3' splice region. Computational tools suggest a possible impact to splicing. However, this information is not predictive enough to determine pathogenicity. The phenotype of individuals compound heterozygous for this variant is high' ly specific for MPS based on their Alpha-L-iduronidase protein levels being <1% consistent with disease (PMID: 9748610, 8213840). In summary, this variant meets criteria to be classified as pathogenic for MPS in an autosomal recessive manner based on the presence of the variant in combination with reported pathogenic variants, the phenotype of patients with the variant being highly specific for MPS, and evidence of aberrant splicing. ACMG/AMP Criteria applied: PM3_very-strong, PM2, PP4, PS3_supporting (Richards 2015).
Natera, Inc. RCV000208601 SCV001461752 likely pathogenic Mucopolysaccharidosis type 1 2020-09-16 no assertion criteria provided clinical testing

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