ClinVar Miner

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

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
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,; 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).

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.