ClinVar Miner

Submissions for variant NM_003361.4(UMOD):c.278_289delinsCCGCCTCCT (p.Val93_Gly97delinsAlaAlaSerCys)

dbSNP: rs878855325
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV002251339 SCV001427125 pathogenic Familial juvenile hyperuricemic nephropathy type 1 2018-06-29 criteria provided, single submitter clinical testing A heterozygous inframe deletion-insertion variant, NM_003361.3(UMOD):c.278_289delinsCCGCCTCCT, has been identified in exon 3 of 11 of the UMOD gene. The variant is predicted to result in an inframe deletion-insertion at position 93 to 97 of the protein (NP_003352.2(UMOD):p.(Val93_Gly97delinsAlaAlaSerCys)). The variant is absent in population databases (gnomAD, dbSNP, 1000G). The variant has been previously described as pathogenic in many patients with either medullary cystic kidney disease type 2 (MCKD2) or UMOD-associated kidney disease (UMAK) (Wolf, M.T.F. et al., 2013, Smith, G.D. et al., 2011, Stewart, A.P. et al., 2015, Kim, Y. et al., 2017). Segregation has been reported with MCKD2 in one family and in four families with UMAK (Wolf, M.T.F. et al., 2013, Smith, G.D. et al., 2011). Protien modelling predictions of this variant demonstrated a loss of disulfide bridging resuting in unfolding of the N-terminal region (Smith, G.D. et al., 2011). Furthermore, in vitro and in vivo studies of this variant demostrated trafficking defects, endoplasmic reticulum retention, and a reduction in the amount of protein secretion (Stewart, A.P. et al., 2015). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
Fulgent Genetics, Fulgent Genetics RCV002251339 SCV001752579 pathogenic Familial juvenile hyperuricemic nephropathy type 1 2022-05-07 criteria provided, single submitter clinical testing
GeneDx RCV002466478 SCV002762400 pathogenic not provided 2022-11-30 criteria provided, single submitter clinical testing Identified in multiple unrelated families with UMOD-associated kidney disease (Smith et al., 2011; Wolf et al., 2003; Chun et al. 2020); reported in Wolf et al. as c.383del12/ins9 due to use of alternate nomenclature; In-frame deletion of 5 amino acids and insertion of 4 different amino acids in a non-repeat region predicted to critically alter the protein; Published functional studies in HEK293 cells demonstrate that c.278_289del12ins effects protein maturation and results in ER retention (Smith et al., 2011), and functional studies in tsA 201 cells demonstrate that c.278_289del12ins results in intracellular protein aggregation and premature polymerization (Stewart et al., 2015); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25436415, 22034507, 14531790, 32274456, 32939031, 20301530)
Mayo Clinic Laboratories, Mayo Clinic RCV002466478 SCV004226905 pathogenic not provided 2023-03-16 criteria provided, single submitter clinical testing PP1_strong, PM2_supporting, PM4, PS3, PS4_moderate
Molecular Genetics, Royal Melbourne Hospital RCV001328178 SCV004812539 pathogenic Autosomal dominant medullary cystic kidney disease with or without hyperuricemia 2023-11-05 criteria provided, single submitter clinical testing This complex sequence change is a deletion of 12 bp and insertion of nine bp, predicted to cause a change in the length of the protein due to an in-frame substitution of five amino acids for four amino acids in a non-repeat region of the UMOD protein, p.(Val93_Gly97delinsAlaAlaSerCys). The variant alters a cysteine residue involved in a disulphide bond in the EGF-like domain 2 (PMID: 35273390, 36038257). This variant is absent from the population database gnomAD v2.1 and v3.1. It has been reported as a British founder variant for hereditary nephropathy and segregates with renal disease in multiple families (PMID: 36038257). The variant demonstrates deficient intracellular trafficking associated with endoplasmic reticulum retention and reduced secretion in multiple in vitro functional assays with limited validation (PMID: 22034507, 32954071). Based on the classification scheme RMH Modified ACMG Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PS4, PP1S, PM1, PM2P, PS3P.
GeneReviews RCV002251339 SCV000291971 not provided Familial juvenile hyperuricemic nephropathy type 1 no assertion provided literature only Common pathogenic variant; associated with less frequent gout, possible association with Later onset of ESRD
Sydney Genome Diagnostics, Children's Hospital Westmead RCV001328178 SCV001449466 likely pathogenic Autosomal dominant medullary cystic kidney disease with or without hyperuricemia 2018-09-05 no assertion criteria provided clinical testing This patient is heterozygous for the variant, c.278_289delinsCCGCCTCCT (p.Val93_Gly97delinsAlaAlaSerCys), in the UMOD gene. This variant, located in a calcium binding EGF domain of UMOD, is likely to be pathogenic as it results in the loss of 5 residues (ValCysProGluGly), including a conserved cysteine at position 94, and the insertion of 4 residues (AlaAlaSerCys). This variant has been previously reported in several members of a family with medullary cystic kidney disease (Wolf et al 2003 Kidney Int 64:1580-1587). This variant is referred to as 383del12/ins9 in this paper.

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