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

dbSNP: rs878855325

Total submissions: 7

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.