Total submissions: 6
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, |
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, |
RCV001248726 | SCV002075329 | pathogenic | Mucopolysaccharidosis type 1 | 2020-12-10 | no assertion criteria provided | clinical testing |