chr16-20348984-C-A

Variant names:

• chr16-20348984-C-A
• rs398123697
• NM_003361.4:c.317G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 10P and 4B. PM1 PM5 PP2 PP3_Strong PP5 BS2

The NM_003361.4(UMOD):​c.317G>T​(p.Cys106Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000445 in 1,574,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C106Y) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: UMOD NM_003361.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:1 O:1
• Conservation: PhyloP100: 4.13
• Publications: 10 publications found

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]

UMOD Gene-Disease associations (from GenCC):

• autosomal dominant medullary cystic kidney disease with or without hyperuricemia

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• glomerulocystic kidney disease with hyperuricemia and isosthenuria

  Inheritance: AD Classification: DEFINITIVE Submitted by: Laboratory for Molecular Medicine
• familial juvenile hyperuricemic nephropathy type 1

  Inheritance: AD, Unknown Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• autosomal dominant medullary cystic kidney disease with hyperuricemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_003361.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-20348984-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 807521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 or without hyperuricemia, familial juvenile hyperuricemic nephropathy type 1, glomerulocystic kidney disease with hyperuricemia and isosthenuria, autosomal dominant medullary cystic kidney disease with hyperuricemia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 16-20348984-C-A is Pathogenic according to our data. Variant chr16-20348984-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 94129.
• BS2: High AC in GnomAdExome4 at 6 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UMOD	NM_003361.4	c.317G>T	p.Cys106Phe	missense_variant	Exon 3 of 11	ENST00000396138.9	NP_003352.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UMOD	ENST00000396138.9	c.317G>T	p.Cys106Phe	missense_variant	Exon 3 of 11	5	NM_003361.4	ENSP00000379442.5
UMOD	ENST00000396134.6	c.416G>T	p.Cys139Phe	missense_variant	Exon 4 of 12	2		ENSP00000379438.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152280 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000109 AC: 2 AN: 184308 AF XY: 0.0000101

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000260

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000422 AC: 6 AN: 1421900 Hom.: 0 Cov.: 39 AF XY: 0.00000426 AC XY: 3 AN XY: 703700

African (AFR) AF: 0.00 AC: 0 AN: 32558

American (AMR) AF: 0.00 AC: 0 AN: 38744

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25424

East Asian (EAS) AF: 0.00 AC: 0 AN: 37350

South Asian (SAS) AF: 0.00 AC: 0 AN: 81398

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49834

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.00000366 AC: 4 AN: 1091942

Other (OTH) AF: 0.0000339 AC: 2 AN: 58930

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152280 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74398

African (AFR) AF: 0.00 AC: 0 AN: 41486

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68050

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000831 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:4 Uncertain:1

May 23, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies suggest abnormal protein folding and aggregation (PMID: 32926855); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32926855, 30099615, 31447099, 32954071, 34746741, 32450155, 35947615, 30586318, 36140271, 31308072, 29212948, 32274456) -

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Oct 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 106 of the UMOD protein (p.Cys106Phe). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with autosomal dominant tubulointerstitial kidney disease (PMID: 32450155). ClinVar contains an entry for this variant (Variation ID: 94129). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt UMOD protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects UMOD function (PMID: 32926855). This variant disrupts the p.Cys106 amino acid residue in UMOD. Other variant(s) that disrupt this residue have been observed in individuals with UMOD-related conditions (PMID: 32450155), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Aug 31, 2017

Blueprint Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 21, 2012

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jun 30, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely 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, possible association with Later onset of ESRD -

Oct 19, 2018

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.317G>T (p.Cys106Phe) variant in the UMOD gene has been reported in two patients affected with autosomal dominant tubulointerstitial kidney disease (ADTKD, PMID 29212948). This variant is identified in one patient with clinical diagnosis of familial ADTKD referred for genetic testing in our laboratory. This variant has never been reported in general population databases and is located in a region where most of the variants associated with kidney disease are reported (PMID 28781372). Two variants in the same codon, p.Cys106Gly and p.Cys106Tyr have also been in reported to associate with ADTKD (PMID 28781372, 20172860) . Therefore, we classify this c.317G>T (p.Cys106Phe) variant in the UMOD gene as likely pathogenic. -

Jan 14, 2021

Johns Hopkins Genomics, Johns Hopkins University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This UMOD variant has been reported in individuals presenting with autosomal dominant tubulointerstitial kidney disease as well as a less common presentation including hematuria, proteinuria, and glomerular and interstitial inflammation. Cys106 is located in the EGF-like domain II, where a cluster of variants associated with kidney disease are reported. A functional study using a mouse homolog of the UMOD p.Cys106Phe variant suggests that misfolded and aggregated uromodulin engages the kidney's immune system, resulting in auto-antibody and immune complex formation. This variant (rs398123697) is rare (<0.1%) in a large population dataset (gnomAD: 2/184308 total alleles; 0.001%; no homozygotes). A bioinformatic tool queried predicts that this substitution would be damaging, and the cysteine residue at this position is highly evolutionarily conserved across most species assessed. This variant has been reported in ClinVar. We consider this variant to be likely pathogenic. -

UMOD-related disorder Pathogenic:1

May 22, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The UMOD c.317G>T variant is predicted to result in the amino acid substitution p.Cys106Phe. This variant has been reported in multiple individuals with tubulointerstitial kidney disease (Devuyst et al. 2017. PubMed ID: 28781372; Kim et al. 2017. PubMed ID: 29212948; Table S7, Groopman et al. 2018. PubMed ID: 30586318; Chun et al. 2020. PubMed ID: 32274456; Olinger et al. 2020. PubMed ID: 32450155; Kidd et al. 2020. PubMed ID: 32954071). Functional studies using a mouse model showed that this variant results in autoantibodies against aggregated misfolded protein with immune complex formation and kidney fibrosis (Plotkin et al. 2020. PubMed ID: 32926855). This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-20360306-C-A). This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	.;.;.;.;T;.;.;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	D;D;D;.;D;D;T;T
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	4.1	.;.;H;H;.;.;.;.
PhyloP100		4.1
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-4.6	D;D;D;.;.;.;.;.
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;D;.;.;.;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D;.;.;D;D
Polyphen		1.0	.;.;D;D;.;.;.;.
Vest4		0.64
MutPred		0.90		.;.;Loss of disorder (P = 0.0951);Loss of disorder (P = 0.0951);.;Loss of disorder (P = 0.0951);.;.;
MVP		0.91
MPC		2.3
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.99
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs398123697; hg19: chr16-20360306;