ClinVar Miner

Submissions for variant NM_000203.5(IDUA):c.1469T>C (p.Leu490Pro) (rs121965027)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000790664 SCV000224792 pathogenic not provided 2012-07-31 criteria provided, single submitter clinical testing
Counsyl RCV000173657 SCV000799455 pathogenic Hurler syndrome 2018-04-18 criteria provided, single submitter clinical testing
Invitae RCV001204340 SCV001375542 pathogenic Mucopolysaccharidosis type 1 2020-02-21 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 490 of the IDUA protein (p.Leu490Pro). The leucine residue is weakly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is present in population databases (rs121965027, ExAC 0.01%). This variant has been observed in individuals affected with mucopolysaccharidosis type I (PMID: 7550232, 27146977, 21394825). ClinVar contains an entry for this variant (Variation ID: 11919). This variant has been reported to affect IDUA protein function (PMID: 7550232). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000012694 SCV000032929 pathogenic Mucopolysaccharidosis, MPS-I-H/S 1995-01-01 no assertion criteria provided literature only
Broad Institute Rare Disease Group, Broad Institute RCV001204340 SCV001422525 likely pathogenic Mucopolysaccharidosis type 1 2020-01-14 no assertion criteria provided curation The p.Leu490Pro variant in IDUA has been reported in at least 20 individuals with mucopolysaccharidosis (MPS) (PMID: 28752568, 7550232, 11735025, 21394825) and has been Identified in 0.026% (6/22666) of South Asian chromosomes and 0.001% (1/69396) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121965027). 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: 11919) as Pathogenic by EGL Genetic Diagnostics, Counsyl, and OMIM. In vitro functional studies provide some evidence that the p.Leu490Pro variant may impact protein function (PMID: 7550232). However, these types of assays may not accurately represent biological function. The phenotype of individuals homozygous for this variant is highly specific for MPS1 based on alpha-l-iduronidase activity being <1% of normal consistent with disease (PMID: 27146977). The presence of this variant in at least 19 affected homozygotes and in combination with a reported pathogenic variant in an individual with MPS increases the likelihood that the p.Leu490Pro variant is pathogenic (VariationID: 556406; PMID: 28752568, 7550232, 11735025, 21394825, 27146977). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM3, PS3_moderate, PM2_supporting, PP4 (Richards 2015).
GeneDx RCV000790664 SCV001803931 pathogenic not provided 2019-01-24 no assertion criteria provided clinical testing Published functional studies demonstrate this variant results in reduced IDUA activity (Tieu et al., 1995); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31589614, 31473686, 31400021, 28752568, 21394825, 27146977, 7550232, 23786846)

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.