Submissions for variant NM_025132.4(WDR19):c.3483+5G>A

gnomAD frequency: 0.00013  dbSNP: rs201216969

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001146557	SCV001307307	uncertain significance	Cranioectodermal dysplasia 4	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001149319	SCV001310263	uncertain significance	Asphyxiating thoracic dystrophy 5	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001202818	SCV001373947	uncertain significance	Asphyxiating thoracic dystrophy 5; Senior-Loken syndrome 8	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change falls in intron 31 of the WDR19 gene. It does not directly change the encoded amino acid sequence of the WDR19 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs201216969, gnomAD 0.02%). This variant has been observed in individual(s) with WDR19-related conditions (PMID: 32483926). ClinVar contains an entry for this variant (Variation ID: 900966). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002276640	SCV002567170	uncertain significance	Connective tissue disorder	2019-08-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002480539	SCV002793783	uncertain significance	Asphyxiating thoracic dystrophy 5; Nephronophthisis 13; Cranioectodermal dysplasia 4; Senior-Loken syndrome 8; Spermatogenic failure 72	2022-03-16	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004538371	SCV004116038	uncertain significance	WDR19-related disorder	2023-04-30	criteria provided, single submitter	clinical testing	The WDR19 c.3483+5G>A variant is predicted to interfere with splicing. This variant is predicted to weaken the adjacent splice donor site based on available splicing prediction programs (Alamut Visual Plus v1.6.1). However, such computer prediction programs are imperfect. This variant was reported in a study of individuals with inherited retinal and optic nerve disorders, however additional information was not provided (Table S12, Diñeiro et al. 2020. PubMed ID: 32483926). This variant is reported in 0.023% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-39271725-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.