ClinVar Miner

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

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Total submissions: 6
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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,; 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)

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