ClinVar Miner

Submissions for variant NM_000203.5(IDUA):c.1037T>G (p.Leu346Arg)

dbSNP: rs121965033
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000012703 SCV000795251 pathogenic Hurler syndrome 2017-11-02 criteria provided, single submitter clinical testing
Invitae RCV001248726 SCV001422232 pathogenic Mucopolysaccharidosis type 1 2024-01-02 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 346 of the IDUA protein (p.Leu346Arg). This variant is present in population databases (rs121965033, gnomAD 0.006%). This missense change has been observed in individual(s) with mucopolysaccharidosis type I (PMID: 10735634, 15521993, 21480867, 21624210, 29801497). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of East Asian ancestry (PMID: 10735634, 15521993, 21480867, 21624210, 29801497). ClinVar contains an entry for this variant (Variation ID: 11927). 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) performed at Invitae indicates that this missense variant is expected to disrupt IDUA protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects IDUA function (PMID: 10735634). For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV001248726 SCV001422673 pathogenic Mucopolysaccharidosis type 1 2020-01-14 criteria provided, single submitter curation The p.Leu346Arg variant in IDUA has been reported in at least 19 individuals with mucopolysaccharidosis (MPS) (PMID: 10735634, 21480867, 27520059) and has been identified in 0.006% (1/18160) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121965033). 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: 11927) as pathogenic by Counsyl and OMIM. In vitro functional studies provide some evidence that the p.Leu346Arg variant may impact protein function (PMID: 10735634). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The phenotype of individuals compound heterozygous for this variant is highly specific for MPS based on alpha-L-iduronidase activity being <1% consistent with disease (PMID: 21480867). The presence of this variant in 4 affected homozygotes and in combination with reported pathogenic or likely pathogenic variants in 5 individuals with MPS1 increases the likelihood that the p.Leu346Arg variant is pathogenic (VariationID: 551563, 11921; PMID: 10735634, 21480867, 27520059). In summary, this variant meets criteria to be classified as pathogenic for MPS in an autosomal recessive manner based on the presence of the variant in the homozygous state and in combination with other pathogenic variants in individuals with MPS, functional studies, and the phenotype of individuals with the variant being highly specific for MPS. ACMG/AMP Criteria applied: PM3_very-strong, PS3, PM2, PP3, PP4 (Richards 2015).
OMIM RCV000012702 SCV000032937 pathogenic Mucopolysaccharidosis, MPS-I-H/S 2004-12-01 no assertion criteria provided literature only
OMIM RCV000012703 SCV000032938 pathogenic Hurler syndrome 2004-12-01 no assertion criteria provided literature only
Natera, Inc. RCV001248726 SCV002075329 pathogenic Mucopolysaccharidosis type 1 2020-12-10 no assertion criteria provided clinical testing

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