ClinVar Miner

Submissions for variant NM_000203.5(IDUA):c.1898C>G (p.Ser633Trp) (rs886043347)

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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 RCV000323838 SCV000339590 pathogenic not provided 2016-02-10 criteria provided, single submitter clinical testing
Ambry Genetics RCV001267071 SCV001445252 pathogenic Inborn genetic diseases 2018-03-12 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV001248897 SCV001422578 likely pathogenic Mucopolysaccharidosis type 1 2020-01-22 no assertion criteria provided curation The p.Ser633Trp variant in IDUA has been reported in at least 4 individuals with mucopolysaccharidosis (MPS) (PMID: 24798265; doi: 10.1016/j.ymgme.2015.12.397) and has been identified in 0.003% (1/34546) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs886043347). 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 as pathogenic by EGL Genetic Diagnostics (Variation ID: 286242). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional pathogenic variant, resulting in a different amino acid change at the same position, p.Ser633Leu, has been reported pathogenic in association with disease in the literature and ClinVar, supporting that a change at this position may not be tolerated (PMID: 16438163, 28752568, 11735025, 2448007; VariationID: 556406). The p.Ser633Trp variant is located in a region of IDUA that is important for protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 24480078). The phenotype of individuals homozygous and compound heterozygous for this variant is highly specific for MPS based on a-L-Iduronidase activity being <1% of normal, consistent with disease (PMID: 24798265; doi: 10.1016/j.ymgme.2015.12.397). The presence of this variant in at least 3 affected homozygotes and in combination with a reported pathogenic variant in an individual with MPS increases the likelihood that the p.Ser633Trp variant is pathogenic (VariationID: 11908; PMID: 24798265; doi: 10.1016/j.ymgme.2015.12.397). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM5, PM3, PP3, PM1_supporting, PP4 (Richards 2015).

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