Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Revvity Omics, |
RCV001781252 | SCV002016684 | likely pathogenic | not provided | 2023-12-01 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV001851808 | SCV002263927 | likely pathogenic | Mucopolysaccharidosis type 1 | 2024-01-16 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 492 of the IDUA protein (p.Arg492Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Scheie syndrome (PMID: 7550232, 21394825). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 11918). 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. Experimental studies have shown that this missense change affects IDUA function (PMID: 7550232). 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, |
RCV001851808 | SCV004037745 | likely pathogenic | Mucopolysaccharidosis type 1 | 2023-08-30 | criteria provided, single submitter | clinical testing | Variant summary: IDUA c.1475G>C (p.Arg492Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 146586 control chromosomes (gnomAD). c.1475G>C has been reported in the literature in individuals affected with Mucopolysaccharidosis Type 1 (examples: Tieu_1995, Bertola_2011, Minter_2018, Voskoboeva_2022). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (examples: Tieu_1995). The following publications have been ascertained in the context of this evaluation (PMID: 21394825, 29120458, 7550232, 35141277). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| OMIM | RCV000012693 | SCV000032928 | pathogenic | Mucopolysaccharidosis, MPS-I-S | 1995-01-01 | no assertion criteria provided | literature only |