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

gnomAD frequency: 0.00004  dbSNP: rs751290509

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000779440	SCV000916060	uncertain significance	WDR19-related disorder	2018-10-23	criteria provided, single submitter	clinical testing	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.
Blueprint Genetics	RCV001074152	SCV001239721	likely pathogenic	Retinal dystrophy	2019-02-04	criteria provided, single submitter	clinical testing
Invitae	RCV001387309	SCV001587907	pathogenic	Asphyxiating thoracic dystrophy 5; Senior-Loken syndrome 8	2024-01-08	criteria provided, single submitter	clinical testing	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.
Molecular Genetics, Royal Melbourne Hospital	RCV002225117	SCV002503712	likely pathogenic	Cranioectodermal dysplasia 4	2022-04-22	criteria provided, single submitter	clinical testing	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.
Clinical Genetics, Academic Medical Center	RCV001701316	SCV001924855	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001701316	SCV001957506	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001701316	SCV002034105	pathogenic	not provided		no assertion criteria provided	clinical testing