ClinVar Miner

Submissions for variant NM_000203.5(IDUA):c.1893del (p.Phe632fs) (rs1553917754)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587377 SCV000695970 likely pathogenic Mucopolysaccharidosis type 1 2020-10-09 criteria provided, single submitter clinical testing Variant summary: IDUA c.1893delC (p.Phe632SerfsX77+) causes a frameshift which results in an extension of the protein. The variant was absent in 248970 control chromosomes (gnomAD). c.1893delC has been reported in the literature in individuals (compound heterozygous and homozygous) affected with Hurler syndrome - a severe form of Mucopolysaccharidosis Type 1 (Bertola_2011, Oussoren_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Counsyl RCV000984187 SCV001132230 likely pathogenic Hurler syndrome 2017-07-25 no assertion criteria provided clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000587377 SCV001423020 likely pathogenic Mucopolysaccharidosis type 1 2020-01-22 no assertion criteria provided curation The p.Phe632Serfs variant in IDUA has been reported in at least 2 individuals with mucopolysaccharidosis (MPS) (PMID: 21394825, 29906569) and was absent from large population studies. This variant has been reported in ClinVar (VariationID: 495733) as likely pathogenic by Integrated Genetics. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 632. This termination codon occurs within the the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the IDUA gene is an established disease mechanism in autosomal recessive MPS. The presence of this variant in an affected homozygote increases the likelihood that the p.Phe632Serfs variant is pathogenic (PMID: 29906569). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1_strong, PM2, PM3_supporting (Richards 2015).

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