rs878855325

chr16-20349011-CCTTCGGGGCAGA-CAGGAGGCGG

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_003361.4(UMOD):c.278_289delinsCCGCCTCCT(p.Val93_Gly97delinsAlaAlaSerCys) variant causes a protein altering change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: UMOD NM_003361.4 protein_altering
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 7.16

Genes affected

UMOD (HGNC:12559): (uromodulin) The protein encoded by this gene is the most abundant protein in mammalian urine under physiological conditions. Its excretion in urine follows proteolytic cleavage of the ectodomain of its glycosyl phosphatidylinosital-anchored counterpart that is situated on the luminal cell surface of the loop of Henle. This protein may act as a constitutive inhibitor of calcium crystallization in renal fluids. Excretion of this protein in urine may provide defense against urinary tract infections caused by uropathogenic bacteria. Defects in this gene are associated with the renal disorders medullary cystic kidney disease-2 (MCKD2), glomerulocystic kidney disease with hyperuricemia and isosthenuria (GCKDHI), and familial juvenile hyperuricemic nephropathy (FJHN). Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-20349012-CTTCGGGGCAGA-AGGAGGCGG is Pathogenic according to our data. Variant chr16-20349012-CTTCGGGGCAGA-AGGAGGCGG is described in ClinVar as [Pathogenic]. Clinvar id is 242346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UMOD	NM_003361.4	c.278_289delinsCCGCCTCCT	p.Val93_Gly97delinsAlaAlaSerCys	protein_altering_variant	3/11	ENST00000396138.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UMOD	ENST00000396138.9	c.278_289delinsCCGCCTCCT	p.Val93_Gly97delinsAlaAlaSerCys	protein_altering_variant	3/11	5	NM_003361.4	P2

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial juvenile hyperuricemic nephropathy type 1 Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 29, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 07, 2022	- -
not provided, no classification provided	literature only	GeneReviews	-	Common pathogenic variant; associated with less frequent gout, possible association with Later onset of ESRD -

Autosomal dominant medullary cystic kidney disease with or without hyperuricemia Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Sydney Genome Diagnostics, Children's Hospital Westmead	Sep 05, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Nov 05, 2023	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. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 30, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 16, 2023	PP1_strong, PM2_supporting, PM4, PS3, PS4_moderate -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs878855325; hg19: chr16-20360334;