ClinVar Genomic variation as it relates to human health

Observed in individuals with autosomal dominant tubulointerstitial kidney disease in published literature, although it is is unknown if these individuals were screened for variants in other genes associated with the phenotype (PMID: 29212948); Published functional studies suggest abnormal protein folding and aggregation (PMID: 32926855); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32926855, 30099615, 32274456, 29212948, 31447099, 32954071, 34746741, 32450155, 35947615, 30586318, 36140271)

The c.317G>T (p.Cys106Phe) variant in the UMOD gene has been reported in two patients affected with autosomal dominant tubulointerstitial kidney disease (ADTKD, PMID 29212948). This variant is identified in one patient with clinical diagnosis of familial ADTKD referred for genetic testing in our laboratory. This variant has never been reported in general population databases and is located in a region where most of the variants associated with kidney disease are reported (PMID 28781372). Two variants in the same codon, p.Cys106Gly and p.Cys106Tyr have also been in reported to associate with ADTKD (PMID 28781372, 20172860) . Therefore, we classify this c.317G>T (p.Cys106Phe) variant in the UMOD gene as likely pathogenic.

This UMOD variant has been reported in individuals presenting with autosomal dominant tubulointerstitial kidney disease as well as a less common presentation including hematuria, proteinuria, and glomerular and interstitial inflammation. Cys106 is located in the EGF-like domain II, where a cluster of variants associated with kidney disease are reported. A functional study using a mouse homolog of the UMOD p.Cys106Phe variant suggests that misfolded and aggregated uromodulin engages the kidney's immune system, resulting in auto-antibody and immune complex formation. This variant (rs398123697) is rare (<0.1%) in a large population dataset (gnomAD: 2/184308 total alleles; 0.001%; no homozygotes). A bioinformatic tool queried predicts that this substitution would be damaging, and the cysteine residue at this position is highly evolutionarily conserved across most species assessed. This variant has been reported in ClinVar. We consider this variant to be likely pathogenic.

The UMOD c.317G>T variant is predicted to result in the amino acid substitution p.Cys106Phe. This variant has been reported in multiple individuals with tubulointerstitial kidney disease (Devuyst et al. 2017. PubMed ID: 28781372; Kim et al. 2017. PubMed ID: 29212948; Table S7, Groopman et al. 2018. PubMed ID: 30586318; Chun et al. 2020. PubMed ID: 32274456; Olinger et al. 2020. PubMed ID: 32450155; Kidd et al. 2020. PubMed ID: 32954071). Functional studies using a mouse model showed that this variant results in autoantibodies against aggregated misfolded protein with immune complex formation and kidney fibrosis (Plotkin et al. 2020. PubMed ID: 32926855). This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-20360306-C-A). This variant is interpreted as likely pathogenic.

This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 106 of the UMOD protein (p.Cys106Phe). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with autosomal dominant tubulointerstitial kidney disease (PMID: 32450155). ClinVar contains an entry for this variant (Variation ID: 94129). 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 UMOD protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects UMOD function (PMID: 32926855). This variant disrupts the p.Cys106 amino acid residue in UMOD. Other variant(s) that disrupt this residue have been observed in individuals with UMOD-related conditions (PMID: 32450155), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

Common pathogenic variant, possible association with Later onset of ESRD