ClinVar Miner

Submissions for variant NM_025132.4(WDR19):c.3875G>T (p.Cys1292Phe)

gnomAD frequency: 0.00001  dbSNP: rs796543493
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ocular Genomics Institute, Massachusetts Eye and Ear RCV001376246 SCV001573320 uncertain significance Senior-Loken syndrome 8 2021-04-08 criteria provided, single submitter research The WDR19 c.3875G>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PP3. Based on this evidence we have classified this variant as Variant of Uncertain Significance.
Invitae RCV001865892 SCV002284390 uncertain significance Asphyxiating thoracic dystrophy 5; Senior-Loken syndrome 8 2022-03-10 criteria provided, single submitter clinical testing 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 1065668). This variant has not been reported in the literature in individuals affected with WDR19-related conditions. 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 replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 1292 of the WDR19 protein (p.Cys1292Phe).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV001376246 SCV005045238 uncertain significance Senior-Loken syndrome 8 2024-05-17 criteria provided, single submitter curation The heterozygous p.Cys1292Phe variant in WDR19 was identified by our study, in the compound heterozygous state, along with a VUS, in one individual with Senior-Loken syndrome 8. However, the phase of these variants are unknown at this time. The variant has been identified in 0.002% (32/1176942) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP (rs796543493)). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has been reported in ClinVar (Variation ID: 1065668) and has been interpreted as uncertain significance by Ocular Genomics Institute, Massachusetts Eye and Ear, and Invitae. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Cys1292Phe variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PP3_Moderate (Richards 2015).

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