ClinVar Miner

Submissions for variant NM_000203.5(IDUA):c.53T>C (p.Leu18Pro) (rs794726878)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000724295 SCV000700757 pathogenic not provided 2016-12-22 criteria provided, single submitter clinical testing
Counsyl RCV000592086 SCV000800112 likely pathogenic Hurler syndrome 2018-05-22 criteria provided, single submitter clinical testing
Mendelics RCV000592086 SCV001136673 uncertain significance Hurler syndrome 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV001248919 SCV001587516 pathogenic Mucopolysaccharidosis type 1 2020-08-26 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 18 of the IDUA protein (p.Leu18Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 25557439, 25256405, 31194252). ClinVar contains an entry for this variant (Variation ID: 193062). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Not Available; Align-GVGD: Class C0). For these reasons, this variant has been classified as Pathogenic.
Broad Institute Rare Disease Group, Broad Institute RCV001248919 SCV001422681 likely pathogenic Mucopolysaccharidosis type 1 2020-01-13 no assertion criteria provided curation The p.Leu18Pro variant in IDUA has been reported in 5 individuals with mucopolysaccharidosis, MSP (PMID: 25256405, 25557439) and was absent from large population studies and no high quality genotypes at this site were noted to include this variant. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The presence of this variant in 3 affected homozygotes and in combination with reported pathogenic variants in 2 individuals with MSP increases the likelihood that the p.Leu18Pro variant is pathogenic (VariationID: 11909, 11908; PMID: 25256405, 25557439). The phenotype of individuals homozygous for this variant is highly specific for MSP based on very low alpha-L-iduronidase activity consistent with disease (PMID: 25256405). The p.Leu18Pro variant is located in a region of IDUA that is essential to protein folding and stability, suggesting that this variant is in a functional domain and supports pathogenicity (PMID: 25256405). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM3_strong, PM1, PM2_supporting, PP4 (Richards 2015).

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