VCV000562322.11 - ClinVar

NM_003361.4(UMOD):c.326T>A (p.Val109Glu)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Likely pathogenic(2); Uncertain significance(2)

4 out of 5 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_003361.4(UMOD):c.326T>A (p.Val109Glu)

Variation ID: 562322 Accession: VCV000562322.11

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16p12.3 16: 20348975 (GRCh38) [ NCBI UCSC ] 16: 20360297 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 1, 2018	Apr 13, 2025	Feb 23, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_003361.4:c.326T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003352.2:p.Val109Glu	missense
NM_001008389.2:c.326T>A
NM_001008389.3:c.326T>A	NP_001008390.1:p.Val109Glu	missense
NM_001278614.2:c.425T>A	NP_001265543.1:p.Val142Glu	missense
NM_001378232.1:c.326T>A	NP_001365161.1:p.Val109Glu	missense
NM_001378233.1:c.326T>A	NP_001365162.1:p.Val109Glu	missense
NM_001378234.1:c.326T>A	NP_001365163.1:p.Val109Glu	missense
NM_001378235.1:c.326T>A	NP_001365164.1:p.Val109Glu	missense
NM_001378237.1:c.326T>A	NP_001365166.1:p.Val109Glu	missense
NR_165456.1:n.551T>A		non-coding transcript variant
NC_000016.10:g.20348975A>T
NC_000016.9:g.20360297A>T
NG_008151.1:g.8741T>A

... more HGVS ... less HGVS

Protein change

V109E, V142E

Other names

Canonical SPDI

NC_000016.10:20348974:A:T

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

The Genome Aggregation Database (gnomAD) 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00003

Exome Aggregation Consortium (ExAC) 0.00004

Links

ClinGen: CA7939460 dbSNP: rs780462125 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
UMOD		-	-	GRCh38 GRCh37	596	617

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Conflicting classifications of pathogenicity (3)	criteria provided, conflicting classifications	Feb 23, 2024	RCV000681768.11
Kidney disorder	Uncertain significance (1)	criteria provided, single submitter	Dec 12, 2016	RCV002294367.2
UMOD-related disorder	Likely pathogenic (1)	criteria provided, single submitter	-	RCV003336129.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Dec 12, 2016) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Kidney disorder	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002587216.1 First in ClinVar: Oct 29, 2022 Last updated: Oct 29, 2022	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (-) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	UMOD-related disorder	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV004046134.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Comment: show This variant has been previously reported as a heterozygous change in patients with kidney disease (PMID: 23988501, 30586318, 33574344). Functional analysis showed that the c.326T>A (p.Val109Glu) variant alters the function of the UMOD protein (PMID: 23988501). The c.326T>A (p.Val109Glu) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.001% (3/215296) and thus is presumed to be rare. The c.326T>A (p.Val109Glu) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.326T>A (p.Val109Glu) variant is classified as Likely Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Uncertain significance (Feb 23, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	not provided	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002231057.4 First in ClinVar: Mar 28, 2022 Last updated: Feb 25, 2025	Publications: PubMed (2) PubMed: 23988501‚ 30586318 Comment: show This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 109 of the UMOD protein (p.Val109Glu). This variant is present in population databases (rs780462125, gnomAD 0.004%). This missense change has been observed in individual(s) with autosomal dominant medullary cystic kidney disease and/or UMOD-related conditions (PMID: 23988501, 30586318). ClinVar contains an entry for this variant (Variation ID: 562322). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on UMOD protein function. Experimental studies have shown that this missense change affects UMOD function (PMID: 23988501). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (Oct 23, 2020) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided (Unknown mechanism)	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001446847.2 First in ClinVar: Nov 28, 2020 Last updated: Apr 13, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Clinical Features: Nephrocalcinosis (present) , Nephrolithiasis (present) , Intellectual disability (present) , Seizure (present) , Global developmental delay (present) , Arachnoid cyst (present) , Hypotonia (present) , Hypocitraturia (present) , Obesity (present) Sex: female

Likely pathogenic (Sep 16, 2018) N Not contributing to aggregate classification	no assertion criteria provided (ACMG Guidelines, 2015)	not provided	Gharavi Laboratory, Columbia University Accession: SCV000809229.1 First in ClinVar: Oct 01, 2018 Last updated: Oct 01, 2018	Observation: 1 Collection method: research Allele origin: germline Affected status: yes Observation 1 Collection method: research Allele origin: germline Affected status: yes

Comment:

This variant has been previously reported as a heterozygous change in patients with kidney disease (PMID: 23988501, 30586318, 33574344). Functional analysis showed that the c.326T>A (p.Val109Glu) variant alters the function of the UMOD protein (PMID: 23988501). The c.326T>A (p.Val109Glu) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.001% (3/215296) and thus is presumed to be rare. The c.326T>A (p.Val109Glu) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.326T>A (p.Val109Glu) variant is classified as Likely Pathogenic.

Comment:

This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 109 of the UMOD protein (p.Val109Glu). This variant is present in population databases (rs780462125, gnomAD 0.004%). This missense change has been observed in individual(s) with autosomal dominant medullary cystic kidney disease and/or UMOD-related conditions (PMID: 23988501, 30586318). ClinVar contains an entry for this variant (Variation ID: 562322). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on UMOD protein function. Experimental studies have shown that this missense change affects UMOD function (PMID: 23988501). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Diagnostic Utility of Exome Sequencing for Kidney Disease.	Groopman EE	The New England journal of medicine	2019	PMID: 30586318
Novel UMOD mutations in familial juvenile hyperuricemic nephropathy lead to abnormal uromodulin intracellular trafficking.	Liu M	Gene	2013	PMID: 23988501

Text-mined citations for rs780462125 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated May 17, 2025