Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002722150 | SCV003018757 | likely pathogenic | Mucopolysaccharidosis type 1 | 2022-09-17 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 533 of the IDUA protein (p.Pro533Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with IDUA-related conditions. 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. This variant disrupts the p.Pro533 amino acid residue in IDUA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1301941, 10911525, 16435195). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004700820 | SCV005202619 | uncertain significance | not specified | 2024-07-11 | criteria provided, single submitter | clinical testing | Variant summary: IDUA c.1598C>A (p.Pro533Gln) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.5e-07 in 1529188 control chromosomes (gnomAD database v4). To our knowledge, no occurrence of c.1598C>A in individuals affected with Mucopolysaccharidosis Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. A different variant affecting the same codon has been classified as pathogenic by our lab (c.1598C>G, p.Pro533Arg) and another (c.1598C>T, p.Pro533Leu), supporting the critical relevance of codon 533 to IDUA protein function. ClinVar contains an entry for this variant (Variation ID: 1970157). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |