ClinVar Miner

Submissions for variant NM_003361.4(UMOD):c.317G>A (p.Cys106Tyr)

dbSNP: rs398123697
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München RCV002251383 SCV001149980 pathogenic Familial juvenile hyperuricemic nephropathy type 1 2018-01-25 criteria provided, single submitter clinical testing
Molecular Genetics, Royal Melbourne Hospital RCV001328229 SCV002503869 pathogenic Autosomal dominant medullary cystic kidney disease with or without hyperuricemia 2024-01-05 criteria provided, single submitter clinical testing This sequence change in UMOD is predicted to replace cysteine with tyrosine at codon 106, p.(Cys106Tyr). The cysteine residue is highly conserved (100 vertebrates, Multiz Alignments), and disrupts a cysteine residue involved in a disulphide bond in the calcium-binding EGF domain (PMID: 23748428). There is a large physicochemical difference between cysteine and tyrosine. This variant is absent from the population database gnomAD v4.0. This variant has been reported in individuals with tubulointerstitial nephropathy and segregates with disease (PMID: 20172860, 29204651, 31822006, 32954071; ClinVar: SCV001449472.1, SCV003841615.1, SCV001149980.1; Royal Melbourne Hospital). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.906). Another missense variant c.317G>T p.(Cys106Phe) in the same codon has been classified as likely pathogenic/pathogenic for tubulointerstitial nephropathy (ClinVar Variation ID: 94129; PMID: 32274456, 32926855). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PM1, PS4_Moderate, PM5, PP1_Moderate, PP3, PM2_Supporting
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV002251383 SCV002557674 likely pathogenic Familial juvenile hyperuricemic nephropathy type 1 2020-05-26 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to tyrosine (exon 3). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (2 heterozygotes, 0 homozygotes). (N) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (2nd EGF-like domain; NCBI, Decipher). (N) 0704 - Comparable variant has low previous evidence for pathogenicity. A different variant in the same codon resulting in a change to phenylalanine has also been reported pathogenic (ClinVar, PMID: 29204651). (P) 0803 - Low previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported as pathogenic in patients with Uromodulin-associated kidney disease (UAKD) (PMID: 20172860) and chronic kidney disease, tubulointerstitial kidney disease, gout and hyperuricaemic nephropathy (PMID: 30773290, PMID: 31509055). (P) 1002 - Moderate functional evidence supporting abnormal protein function. Cysteines in UMOD gene are involved in structurally important disulphide bridges. The interruption of these bonds has been proven for multiple variants affecting cysteines, leading to impaired trafficking of the protein to the cell membrane (PMID: 23748428, PMID: 28781372). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) – Benign
Fulgent Genetics, Fulgent Genetics RCV002251383 SCV002813902 pathogenic Familial juvenile hyperuricemic nephropathy type 1 2022-01-03 criteria provided, single submitter clinical testing
3billion RCV002251383 SCV003841615 pathogenic Familial juvenile hyperuricemic nephropathy type 1 2023-02-23 criteria provided, single submitter clinical testing The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.88; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000807521). A different missense change at the same codon (p.Cys106Phe) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000094129). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Sydney Genome Diagnostics, Children's Hospital Westmead RCV001328229 SCV001449472 likely pathogenic Autosomal dominant medullary cystic kidney disease with or without hyperuricemia 2017-09-15 no assertion criteria provided clinical testing This patient is heterozygous for a c.317G>A p.(Cys106Tyr) in the UMOD gene. To our knowledge, this variant has not been reported in any population databases (i.e. ExAC, ESP or dbSNP). The c.317G>A p.(Cys106Tyr) has been reported in a patient with uromodulin associated kidney disease (Zaucke et al. Hum Mol Genet 2010; 19(10): 1985-1997). The p.Cys106 residue is a highly conserved amino acid (up to 12 species) and there is also a large physicochemical difference between the wild type cysteine and mutant tyrosine. In silico analysis (Alamut Visual v2.8.1) using SIFT, PolyPhen2 and MutationTaster all predict that this variant is likely to be pathogenic. This variant is considered to be likely pathogenic according to the ACMG guidelines.
Yale Center for Mendelian Genomics, Yale University RCV002251383 SCV002106607 likely pathogenic Familial juvenile hyperuricemic nephropathy type 1 2019-02-14 no assertion criteria provided literature only

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