ClinVar Miner

Submissions for variant NM_025132.4(WDR19):c.56T>G (p.Phe19Cys)

gnomAD frequency: 0.00001  dbSNP: rs1247231925
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Rare Disease Group, Clinical Genetics, Karolinska Institutet RCV000754961 SCV000788387 uncertain significance Jeune thoracic dystrophy 2018-05-01 criteria provided, single submitter research
Invitae RCV001236163 SCV001408876 uncertain significance Asphyxiating thoracic dystrophy 5; Senior-Loken syndrome 8 2021-01-12 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with WDR19-related conditions. ClinVar contains an entry for this variant (Variation ID: 558760). This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with cysteine at codon 19 of the WDR19 protein (p.Phe19Cys). The phenylalanine residue is moderately conserved and there is a large physicochemical difference between phenylalanine and cysteine.
Molecular Genetics, Royal Melbourne Hospital RCV002225112 SCV002503640 uncertain significance Cranioectodermal dysplasia 4 2020-05-28 criteria provided, single submitter clinical testing This sequence change is predicted to replace phenylalanine with cysteine at codon 19 of the WDR19 protein (p.Phe19Cys). The phenylalanine residue is highly conserved (100 vertebrates, UCSC), and located in WD repeat 1. There is a large physicochemical difference between phenylalanine and cysteine. The variant is present in a large population cohort at a frequency of 0.001%, which is consistent with a recessive condition (PM2; rs1247231925, 2/170,202 alleles, 0 homozygotes in gnomAD v2.1). The variant has been identified in at least two cases with ciliopathies: compound heterozygous with a variant of uncertain significance in an individual with a phenotype suggestive of shot-rib thoracic dysplasia (SCV000788387.1), and with a second likely pathogenic allele (phase unknown) in an individual with a phenotype suggestive of cranioectodermal dysplasia (PM3_Supporting; Royal Melbourne Hospital). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (PP3; 6/7 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as VARIANT OF UNCERTAIN SIGNIFICANCE . Following criteria are met: PM2, PM3_Supporting, PP3.

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