chr16-20349012-CTTCGGGGCAGA-AGGAGGCGG

Variant names:

• chr16-20349012-CTTCGGGGCAGA-AGGAGGCGG
• rs878855325
• NM_003361.4:c.278_289delTCTGCCCCGAAGinsCCGCCTCCT

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM2 PM4_Supporting PP2 PP5_Very_Strong

The NM_003361.4(UMOD):​c.278_289delTCTGCCCCGAAGinsCCGCCTCCT​(p.Val93_Gly97delinsAlaAlaSerCys) variant causes a missense, disruptive inframe deletion 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 missense, disruptive_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 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

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_003361.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_003361.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 69 curated pathogenic missense variants (we use a threshold of 10). The gene has 14 curated benign missense variants. Gene score misZ: 0.99836 (below the threshold of 3.09). Trascript score misZ: 0.48416 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal dominant medullary cystic kidney disease with hyperuricemia, autosomal dominant medullary cystic kidney disease with or without hyperuricemia, glomerulocystic kidney disease with hyperuricemia and isosthenuria, familial juvenile hyperuricemic nephropathy type 1.
• 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 rank	MANE	Protein	UniProt
UMOD	NM_003361.4	c.278_289delTCTGCCCCGAAGinsCCGCCTCCT	p.Val93_Gly97delinsAlaAlaSerCys	missense_variant, disruptive_inframe_deletion		ENST00000396138.9	NP_003352.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UMOD	ENST00000396138.9	c.278_289delTCTGCCCCGAAGinsCCGCCTCCT	p.Val93_Gly97delinsAlaAlaSerCys	missense_variant, disruptive_inframe_deletion		5	NM_003361.4	ENSP00000379442.5
UMOD	ENST00000396134.6	c.377_388delTCTGCCCCGAAGinsCCGCCTCCT	p.Val126_Gly130delinsAlaAlaSerCys	missense_variant, disruptive_inframe_deletion		2		ENSP00000379438.2

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:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial juvenile hyperuricemic nephropathy type 1 Pathogenic:3 Other:1

Oct 09, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant negative is a known mechanism of disease in this gene and is associated with tubulointerstitial kidney disease 1 (MIM#162000) (PMID: 22117067). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0216 - In-frame insertion/deletion in a non-repetitive region that has low conservation. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - Multiple alternative amino acid changes encompassed by this inframe deletion insertion have been observed in gnomAD (v2) (highest allele count: 2 heterozygotes, 0 homozygotes). (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants, the calcium-binding EGF domain (DECIPHER, PMID: 30099615). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple families with UMOD-related tubulointerstitial kidney disease (ClinVar, PMIDs: 14531790, 22034507, 32274456). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies show that this variant causes trafficking defects and endoplasmic reticulum retention, resulting in premature intracellular polymerization (ClinVar, PMID: 22034507, 25436415). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Mar 18, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Common pathogenic variant; associated with less frequent gout, possible association with Later onset of ESRD -

Dec 23, 2017

Genomics England Pilot Project, Genomics England

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Sep 05, 2018

Sydney Genome Diagnostics, Children's Hospital Westmead

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: 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. -

Aug 05, 2024

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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). The estimated population minor allele frequency in the population database gnomAD v4.1 for this complex variant is 0.001% (13/1,165,668 alleles) in the European (non-Finnish) population. 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 v1.7.0, this variant is classified as PATHOGENIC. Following criteria are met: PS4, PP1_Strong, PM1, PM2_Supporting, PS3_Supporting. -

not provided Pathogenic:2

Mar 16, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_strong, PM2_supporting, PM4, PS3, PS4_moderate -

Nov 30, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mutation Taster		=0/200	disease causing

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;