ClinVar Miner

Submissions for variant NM_003361.3(UMOD):c.317G>T (p.Cys106Phe) (rs398123697)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000681797 SCV000111987 uncertain significance not provided 2012-08-21 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000681797 SCV000927388 likely pathogenic not provided 2017-08-31 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV001258098 SCV001434943 likely pathogenic Familial juvenile hyperuricemic nephropathy type 1 2018-10-19 criteria provided, single submitter clinical testing 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.
Johns Hopkins Genomics, Johns Hopkins University RCV001290381 SCV001478436 likely pathogenic Autosomal dominant medullary cystic kidney disease with hyperuricemia 2021-01-14 criteria provided, single submitter clinical testing 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.
Gharavi Laboratory,Columbia University RCV000681797 SCV000809264 likely pathogenic not provided 2018-09-16 no assertion criteria provided research

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