Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Molecular Genetics, |
RCV003994656 | SCV004812450 | uncertain significance | Autosomal dominant medullary cystic kidney disease with or without hyperuricemia | 2023-03-30 | criteria provided, single submitter | clinical testing | This sequence change in UMOD is predicted to replace proline with glutamine at codon 173, p.(Pro173Gln). The proline residue is highly conserved (87/93 vertebrates, UCSC), and is not located in an annotated domain. There is a moderate physicochemical difference between proline and glutamine. This variant is absent from the population database gnomAD v2.1 and v3.1. To our knowledge, this variant has not been reported in the literature. It has been identified in an individual with a clinical diagnosis of autosomal dominant tubulointerstitial kidney disease (ADTKD; Royal Melbourne Hospital). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Multiple missense variants in the same codon have been reported in individuals with ADTKD, suggesting the importance of the residue p.Pro173 to protein function (PMID: 28509303, 30473401, 32954071). One of these missense variants, c.517C>G p.Pro173Ala (with a small physicochemical difference) has can be classified as likely pathogenic for ADTKD (PMID: 30473401). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM5, PS4_Supporting, PM2_Supporting, PP3. |