Submissions for variant NM_025132.4(WDR19):c.781dup (p.Thr261fs)

gnomAD frequency: 0.00004  dbSNP: rs748656635

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000779441	SCV000916061	uncertain significance	WDR19-related disorder	2018-01-16	criteria provided, single submitter	clinical testing	The WDR19 c.781dupA (p.Thr261AsnfsTer13) frameshift variant has been reported in three studies, where it was found in a compound heterozygous state with a missense variant in one individual and in a heterozygous state in three individuals in whom a second variant was not identified (Halbritter et al. 2013; Coussa et al. 2013; Zhang et al. 2018). The compound heterozygous individual and two of the heterozygous individuals showed features of asphyxiating thoracic dystrophy; one of these heterozygotes also exhibited night blindness and was diagnosed with Senior-Løken syndrome. The third heterozygous individual had isolated nephronophthisis. The p.Thr261AsnfsTer13 variant was absent from at least 192 healthy control subjects and is reported at a frequency of 0.000079 in the European (non-Finnish) population of the Genome Aggregation Database. Functional studies have not been conducted for the p.Thr261AsnfsTer13 variant, which occurs in the fifth WD40 repeat domain of the protein. Due to the limited evidence available and the potential impact of frameshift variants, the p.Thr261AsnfsTer13 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.
Baylor Genetics	RCV000850616	SCV000992849	pathogenic	Nephronophthisis 13; Senior-Loken syndrome 8	2017-12-31	criteria provided, single submitter	clinical testing
Invitae	RCV001231474	SCV001403998	pathogenic	Asphyxiating thoracic dystrophy 5; Senior-Loken syndrome 8	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr261Asnfs*13) 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 (rs748656635, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with asphyxiating thoracic dystrophy (PMID: 28973083, 29068549). ClinVar contains an entry for this variant (Variation ID: 446634). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV003139712	SCV003821817	pathogenic	not provided	2022-01-18	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017660	SCV004847388	pathogenic	Asphyxiating thoracic dystrophy 5	2023-12-04	criteria provided, single submitter	clinical testing	The p.Thr261AsnfsX13 variant in WDR19 has been reported in the compound heterozygous state with another WDR19 variant in at least 2 individuals with clinical features of WDR19-associated ciliopathies (including asphyxiating thoracic dystrophy and/or nephronophthisis). It was also reported in the heterozygous state in 3 individuals with clinical features consistent with WDR-19 associated ciliopathies where a second variant was not identified (Halbritter 2013 PMID: 23559409, Coussa 2013 PMID: 23683095, Meng 2017 PMID: 28973083, Zhang 2018 PMID: 29068549, Liu 2019 PMID: 31216405). This variant has been reported by other clinical laboratories in ClinVar (Variation ID 446634) and has been identified in 0.007% (3/41448) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2), at a frequency low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 261 and leads to a premature termination codon 13 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function variants in WDR19 gene have been reported in individuals with autosomal recessive ciliopathies (Bredrup 2011 PMID: 22019273, Zhang 2018 PMID: 29068549). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive WDR19-associated ciliopathies. ACMG/AMP Criteria applied: PVS1, PM3, PM2_Supporting.
Dan Cohn Lab, University Of California Los Angeles	RCV000515920	SCV000612046	pathogenic	Jeune thoracic dystrophy	2017-06-01	no assertion criteria provided	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV000515920	SCV001479399	likely pathogenic	Jeune thoracic dystrophy		no assertion criteria provided	research