Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Nx |
RCV001374701 | SCV001571611 | likely pathogenic | Hurler syndrome | 2021-01-27 | criteria provided, single submitter | clinical testing | This missense variant (c.1883G>C) in a hotspot (PM1) on exon 14 of the IDUA gene results in a significant change in size and physicochemical properties of the amino acid (p.R628P). This variant has a low allele frequency in GnomAD exomes and is not found in GnomAD genomes (PM2). In silico models generally predict pathogenicity, per Ou et al. PMID 28676128 (PP3). UniProt classifies this variant as Pathogenic and associates it with Hurler-Scheie Syndrome citing Matte et al. PMID 12559846, who report 2 patients and a functional study in CHO cells demonstrating minimal residual activity (PP5). An additional affected compound heterozygote (Q380R/R628P) is reported in Munoz-Rojas et al. PMID 18792977. We interpret c.1883G>C to be likely pathogenic. |
| Revvity Omics, |
RCV001780270 | SCV002016674 | likely pathogenic | not provided | 2023-04-26 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001865868 | SCV002247727 | likely pathogenic | Mucopolysaccharidosis type 1 | 2023-06-22 | criteria provided, single submitter | clinical testing | This variant is present in population databases (rs200448421, gnomAD 0.007%). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects IDUA function (PMID: 12559846). 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. ClinVar contains an entry for this variant (Variation ID: 1064675). This missense change has been observed in individual(s) with mucopolysaccharidosis type 1 (PMID: 12559846, 18792977). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 628 of the IDUA protein (p.Arg628Pro). |
| Foundation for Research in Genetics and Endocrinology, |
RCV003229620 | SCV003926587 | pathogenic | Mucopolysaccharidosis, MPS-IV-A | 2023-05-25 | criteria provided, single submitter | clinical testing | A Heterozygous variation in exon 14 of the IDUA gene that results in the amino acid substitution of proline for arginine at codon 628 was detected. The observed variant c.1883G>C (p.Arg628Pro) has not been reported in the 1000 genomes and MAF of 0.0004% in gnomAD databases. The in silico prediction of the variant are possibly damaging by PolyPhen-2, SIFT, CADD and MutationTaster. In summary, the variant meets our criteria to be classified as pathogenic. |