ClinVar Miner

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

gnomAD frequency: 0.00004  dbSNP: rs587777352
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp 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
GeneDx RCV000681868 SCV005202109 likely pathogenic not provided 2023-11-17 criteria provided, single submitter clinical testing Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29121203, 23559409, 30586318, 26489029, 29068549)
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

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