Submissions for variant NM_025132.4(WDR19):c.3565+1G>A

gnomAD frequency: 0.00004  dbSNP: rs587777352

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001212609	SCV001384198	pathogenic	Asphyxiating thoracic dystrophy 5; Senior-Loken syndrome 8	2023-06-11	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 127159). Disruption of this splice site has been observed in individuals with ciliopathy disorders (PMID: 23559409, 29068549). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change affects a donor splice site in intron 32 of the WDR19 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in WDR19 are known to be pathogenic (PMID: 22019273, 23559409, 23683095, 26275793, 27241786, 29068549).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797626	SCV002041776	pathogenic	Nephronophthisis 13	2021-11-15	criteria provided, single submitter	clinical testing	Variant summary: WDR19 c.3565+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.6e-05 in 227094 control chromosomes. c.3565+1G>A has been reported in the literature as a compound heterozygous genotype in comprehensively analyzed individuals with nephronophthisis-related ciliopathy and/or skeletal ciliopathies such as asphyxiating thoracic dystrophy (ATD) (example, Halbritter_2013, Braun_2016, Zhang_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002277157	SCV002567172	likely pathogenic	Connective tissue disorder	2019-07-01	criteria provided, single submitter	clinical testing
OMIM	RCV000115015	SCV000148924	pathogenic	Senior-Loken syndrome 8	2013-08-01	no assertion criteria provided	literature only
Dan Cohn Lab, University Of California Los Angeles	RCV000516054	SCV000612044	pathogenic	Jeune thoracic dystrophy	2017-06-01	no assertion criteria provided	research
Gharavi Laboratory, Columbia University	RCV000681868	SCV000809347	pathogenic	not provided	2018-09-16	no assertion criteria provided	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV000516054	SCV001479397	likely pathogenic	Jeune thoracic dystrophy		no assertion criteria provided	research
Genomics And Bioinformatics Analysis Resource, Columbia University	RCV000115015	SCV004024137	pathogenic	Senior-Loken syndrome 8		no assertion criteria provided	research