VCV000000873.10 - ClinVar

NM_006953.4(UPK3A):c.818C>T (p.Pro273Leu)

Germline

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.

(4)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_006953.4(UPK3A):c.818C>T (p.Pro273Leu)

Variation ID: 873 Accession: VCV000000873.10

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 22q13.31 22: 45295673 (GRCh38) [ NCBI UCSC ] 22: 45691554 (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	Jan 11, 2019	Oct 8, 2024	Dec 23, 2019

HGVS

Nucleotide	Protein	Molecular consequence
NM_006953.4:c.818C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_008884.1:p.Pro273Leu	missense
NM_001167574.2:c.455C>T	NP_001161046.1:p.Pro152Leu	missense
NC_000022.11:g.45295673C>T
NC_000022.10:g.45691554C>T
NG_016203.2:g.15687C>T
	O75631:p.Pro273Leu

... more HGVS ... less HGVS

Protein change

P273L, P152L

Other names

Canonical SPDI

NC_000022.11:45295672:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

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.

0.00040 (T)

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

1000 Genomes Project 0.00040

1000 Genomes Project 30x 0.00047

Exome Aggregation Consortium (ExAC) 0.00122

The Genome Aggregation Database (gnomAD), exomes 0.00123

Trans-Omics for Precision Medicine (TOPMed) 0.00135

The Genome Aggregation Database (gnomAD) 0.00136

Links

ClinGen: CA114594 UniProtKB: O75631#VAR_044401 OMIM: 611559.0001 dbSNP: rs121918186 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.
UPK3A		-	-	GRCh38 GRCh37	70	143

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.
Congenital anomalies of kidney and urinary tract 1	Uncertain significance (1)	no assertion criteria provided	Jul 1, 2005	RCV000000921.6
Renal hypodysplasia/aplasia 1	Uncertain significance (1)	criteria provided, single submitter	Apr 27, 2017	RCV001150740.5
UPK3A-related disorder	Uncertain significance (1)	no assertion criteria provided	Dec 19, 2023	RCV003415610.6
not provided	Uncertain significance (1)	criteria provided, single submitter	Dec 23, 2019	RCV003488317.2

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.	More information 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 (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Renal hypodysplasia/aplasia 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001311828.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Uncertain significance (Dec 23, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV004237509.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024
Uncertain significance (Jul 01, 2005)	no assertion criteria provided Method: literature only	RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000021071.4 First in ClinVar: Apr 04, 2013 Last updated: Jan 11, 2019	Publications: PubMed (1) PubMed: 15888565 Comment on evidence: This variant, formerly titled RENAL ADYSPLASIA/UROGENITAL ADYSPLASIA, has been reclassified because its contribution to congenital anomalies of the kidney and urogenital tract (see 610805) has … (more) This variant, formerly titled RENAL ADYSPLASIA/UROGENITAL ADYSPLASIA, has been reclassified because its contribution to congenital anomalies of the kidney and urogenital tract (see 610805) has not been confirmed. Jenkins et al. (2005) identified a de novo heterozygous 818C-T transition in exon 6 of the UPK3A gene, resulting in a pro273-to-leu (P273L) substitution in a highly conserved residue, in 2 unrelated patients with renal adysplasia. One patient had unilateral right renal aplasia. Her left kidney had abnormal cortical echogenicity, a malformed pelvis, and a tortuous ureter that resulted in severe vesicoureteral reflux. The urinary bladder had 2 diverticula and there was a common passageway between rectum and urethra. She also had no vaginal orifice, absence of the right uterine horn, and a persistent cloaca. The second patient presented with renal failure at age 2 years. Both kidneys were present, but showed increased cortical echogenicity and thinned parenchyma on imaging. He had bilateral hydronephrosis with severe bilateral vesicoureteral reflux into tortuous ureters. The P273L substitution was predicted to alter the secondary structure of the C terminus. However, in vitro functional expression studies suggested that the mutant protein acted similar to wildtype. (less)
Uncertain significance (Dec 19, 2023)	no assertion criteria provided Method: clinical testing	UPK3A-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004113653.3 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: The UPK3A c.818C>T variant is predicted to result in the amino acid substitution p.Pro273Leu. This variant was reported to occur de novo in two individuals … (more) The UPK3A c.818C>T variant is predicted to result in the amino acid substitution p.Pro273Leu. This variant was reported to occur de novo in two individuals with renal dysplasia and vesicoureteral reflux (Jenkins et al 2005. PubMed ID: 15888565; Dopazo J et al 2016. PubMed ID: 26764160). This variant was also reported as a variant of uncertain significance in a patient with multicystic kidney dysplasia (Nicolaou N et al 2016. PubMed ID: 26489027). This variant is reported in 0.21% of alleles in individuals of European (Non-Finnish) descent in gnomAD which seems too common to be a primary cause of disease. Although we suspect this variant is benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

The UPK3A c.818C>T variant is predicted to result in the amino acid substitution p.Pro273Leu. This variant was reported to occur de novo in two individuals with renal dysplasia and vesicoureteral reflux (Jenkins et al 2005. PubMed ID: 15888565; Dopazo J et al 2016. PubMed ID: 26764160). This variant was also reported as a variant of uncertain significance in a patient with multicystic kidney dysplasia (Nicolaou N et al 2016. PubMed ID: 26489027). This variant is reported in 0.21% of alleles in individuals of European (Non-Finnish) descent in gnomAD which seems too common to be a primary cause of disease. Although we suspect this variant is benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
De novo Uroplakin IIIa heterozygous mutations cause human renal adysplasia leading to severe kidney failure.	Jenkins D	Journal of the American Society of Nephrology : JASN	2005	PMID: 15888565

Text-mined citations for rs121918186 ...

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 Oct 13, 2024

ClinVar Genomic variation as it relates to human health

NM_006953.4(UPK3A):c.818C>T (p.Pro273Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121918186 ...