VCV000632439.17 - ClinVar

NM_025132.4(WDR19):c.641T>A (p.Leu214Ter)

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.

(8)

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.

Conflicting classifications of pathogenicity
Pathogenic(2); Likely pathogenic(2); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_025132.4(WDR19):c.641T>A (p.Leu214Ter)

Variation ID: 632439 Accession: VCV000632439.17

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4p14 4: 39205191 (GRCh38) [ NCBI UCSC ] 4: 39206811 (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	May 27, 2019	Oct 8, 2024	Jan 8, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_025132.4:c.641T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_079408.3:p.Leu214Ter	nonsense
NM_001317924.2:c.161T>A	NP_001304853.1:p.Leu54Ter	nonsense
NC_000004.12:g.39205191T>A
NC_000004.11:g.39206811T>A
NG_031813.1:g.27788T>A

... more HGVS ... less HGVS

Protein change

L214*, L54*

Other names

Canonical SPDI

NC_000004.12:39205190:T:A

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.

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

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00002

The Genome Aggregation Database (gnomAD) 0.00004

Trans-Omics for Precision Medicine (TOPMed) 0.00004

Links

dbSNP: rs751290509 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.
WDR19		-	-	GRCh38 GRCh37	1073	1101

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.
WDR19-related disorder	Uncertain significance (1)	criteria provided, single submitter	Oct 23, 2018	RCV000779440.4
Retinal dystrophy	Likely pathogenic (1)	criteria provided, single submitter	Feb 4, 2019	RCV001074152.2
Asphyxiating thoracic dystrophy 5 Senior-Loken syndrome 8	Pathogenic (1)	criteria provided, single submitter	Jan 8, 2024	RCV001387309.5
not provided	Pathogenic (4)	criteria provided, single submitter	Oct 5, 2023	RCV001701316.6
Cranioectodermal dysplasia 4	Likely pathogenic (1)	criteria provided, single submitter	Apr 22, 2022	RCV002225117.2

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 (Oct 23, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	WDR19-Related Disorders Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000916060.1 First in ClinVar: May 27, 2019 Last updated: May 27, 2019	Comment: The WDR19 c.641T>A (p.Leu214Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. A literature search was … (more) The WDR19 c.641T>A (p.Leu214Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. The variant is reported at a frequency of 0.000034 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the potential impact of stop-gained variants, the p.Leu214Ter variant is classified as a variant of unknown significance but suspicious for pathogenicity for WDR19-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
Likely pathogenic (Feb 04, 2019)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Retinal dystrophy Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001239721.1 First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 Comment: My Retina Tracker patient
Pathogenic (Jan 08, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Senior-Loken syndrome 8 Asphyxiating thoracic dystrophy 5 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001587907.4 First in ClinVar: May 10, 2021 Last updated: Feb 28, 2024	Publications: PubMed (7) PubMed: 22019273‚ 23559409‚ 23683095‚ 26275793‚ 27241786‚ 29068549‚ 34295353 Comment: This sequence change creates a premature translational stop signal (p.Leu214) in the WDR19 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Leu214) in the WDR19 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in WDR19 are known to be pathogenic (PMID: 22019273, 23559409, 23683095, 26275793, 27241786, 29068549). This variant is present in population databases (rs751290509, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with clinical features of WDR19-related conditions (PMID: 34295353). ClinVar contains an entry for this variant (Variation ID: 632439). For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (Apr 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cranioectodermal dysplasia 4 Affected status: yes Allele origin: germline	Molecular Genetics, Royal Melbourne Hospital Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002503712.2 First in ClinVar: Apr 28, 2022 Last updated: Apr 15, 2024	Publications: PubMed (1) PubMed: 22019273 Comment: This sequence change creates a premature termination codon at position 214 in exon 8 (of 37) of WDR19, p.(Leu214). It is expected to result in … (more) This sequence change creates a premature termination codon at position 214 in exon 8 (of 37) of WDR19, p.(Leu214). It is expected to result in nonsense-mediated decay in a gene where loss of function is an established mechanism of disease (PMID: 22019273). The variant is present in a large population cohort at a frequency of 0.002%, which is consistent with a recessive condition (rs751290509, 5/258,002 alleles, 0 homozygotes in gnomAD v2.1). The variant has been not been reported in the relevant medical literature and has been reported as likely pathogenic (ClinVar ID: 632439). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PVS1, PM2. (less)
Pathogenic (Oct 05, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005332545.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: Identified in a patient with renal hypoplasia in the published literature (Wang et al., 2021); Nonsense variant predicted to result in protein truncation or nonsense … (more) Identified in a patient with renal hypoplasia in the published literature (Wang et al., 2021); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 34295353) (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001924855.1 First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001957506.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV002034105.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021

Comment:

The WDR19 c.641T>A (p.Leu214Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. The variant is reported at a frequency of 0.000034 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the potential impact of stop-gained variants, the p.Leu214Ter variant is classified as a variant of unknown significance but suspicious for pathogenicity for WDR19-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Comment:

This sequence change creates a premature translational stop signal (p.Leu214*) in the WDR19 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in WDR19 are known to be pathogenic (PMID: 22019273, 23559409, 23683095, 26275793, 27241786, 29068549). This variant is present in population databases (rs751290509, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with clinical features of WDR19-related conditions (PMID: 34295353). ClinVar contains an entry for this variant (Variation ID: 632439). For these reasons, this variant has been classified as Pathogenic.

Comment:

This sequence change creates a premature termination codon at position 214 in exon 8 (of 37) of WDR19, p.(Leu214*). It is expected to result in nonsense-mediated decay in a gene where loss of function is an established mechanism of disease (PMID: 22019273). The variant is present in a large population cohort at a frequency of 0.002%, which is consistent with a recessive condition (rs751290509, 5/258,002 alleles, 0 homozygotes in gnomAD v2.1). The variant has been not been reported in the relevant medical literature and has been reported as likely pathogenic (ClinVar ID: 632439). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PVS1, PM2.

Comment:

Identified in a patient with renal hypoplasia in the published literature (Wang et al., 2021); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 34295353)

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
Spectrum of Mutations in Pediatric Non-glomerular Chronic Kidney Disease Stages 2-5.	Wang X	Frontiers in genetics	2021	PMID: 34295353
Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies.	Zhang W	Human mutation	2018	PMID: 29068549
Next-generation sequencing for diagnosis of rare diseases in the neonatal intensive care unit.	Daoud H	CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne	2016	PMID: 27241786
Reproductive genetic counseling challenges associated with diagnostic exome sequencing in a large academic private reproductive genetic counseling practice.	Westerfield LE	Prenatal diagnosis	2015	PMID: 26275793
WDR19: an ancient, retrograde, intraflagellar ciliary protein is mutated in autosomal recessive retinitis pigmentosa and in Senior-Loken syndrome.	Coussa RG	Clinical genetics	2013	PMID: 23683095
Identification of 99 novel mutations in a worldwide cohort of 1,056 patients with a nephronophthisis-related ciliopathy.	Halbritter J	Human genetics	2013	PMID: 23559409
Ciliopathies with skeletal anomalies and renal insufficiency due to mutations in the IFT-A gene WDR19.	Bredrup C	American journal of human genetics	2011	PMID: 22019273

Text-mined citations for rs751290509 ...

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 08, 2024

ClinVar Genomic variation as it relates to human health

NM_025132.4(WDR19):c.641T>A (p.Leu214Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs751290509 ...