ClinVar Miner

Submissions for variant NM_000203.5(IDUA):c.923T>C (p.Leu308Pro)

gnomAD frequency: 0.00006  dbSNP: rs752337969
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000595653 SCV000708904 uncertain significance not provided 2017-06-29 criteria provided, single submitter clinical testing
Counsyl RCV000668685 SCV000793327 uncertain significance Hurler syndrome 2017-08-10 criteria provided, single submitter clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV001248917 SCV001422674 uncertain significance Mucopolysaccharidosis type 1 2020-01-13 criteria provided, single submitter curation The p.Leu308Pro variant in IDUA has been reported in the homozygous state in 2 Mexican individuals with mucopolysaccharidosis (MPS), segregated with disease in 2 affected relatives from 1 family (PMID: 21393040), and has been identified in 0.005% (1/19128) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs752337969). 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: 502243) as a VUS by EGL Genetic Diagnostics and Counsyl. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. Two affected individuals with this variant were also homozygous for a reported pathogenic variant in another gene known to be associated with another type of MPS (VariationID: 550542). However, these two affected individuals have phenotypes that appear to be consistent with both types of MPS, raising the possibility that this variant is also pathogenic (PMID: 21393040). In summary, the clinical significance of the p.Leu308Pro variant is uncertain. ACMG/AMP Criteria applied: PM2 (Richards 2015).
Invitae RCV001248917 SCV003525753 pathogenic Mucopolysaccharidosis type 1 2023-10-14 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 308 of the IDUA protein (p.Leu308Pro). This variant is present in population databases (rs752337969, gnomAD 0.005%). This missense change has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 21393040). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 502243). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on IDUA protein function. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity RCV000595653 SCV003809914 uncertain significance not provided 2023-07-18 criteria provided, single submitter clinical testing

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