ClinVar Miner

Submissions for variant NM_025132.4(WDR19):c.2129T>C (p.Leu710Ser)

gnomAD frequency: 0.00003  dbSNP: rs387906980
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Mendelics RCV000987440 SCV001136730 pathogenic Asphyxiating thoracic dystrophy 5 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV001047050 SCV001210982 pathogenic Asphyxiating thoracic dystrophy 5; Senior-Loken syndrome 8 2021-11-27 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 710 of the WDR19 protein (p.Leu710Ser). This variant is present in population databases (rs387906980, gnomAD 0.003%). This missense change has been observed in individual(s) with Sensenbrenner syndrome (PMID: 22019273, 23683095, 27241786). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30703). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). For these reasons, this variant has been classified as Pathogenic.
Ocular Genomics Institute, Massachusetts Eye and Ear RCV000169775 SCV001573264 pathogenic Senior-Loken syndrome 8 2021-04-08 criteria provided, single submitter research The WDR19 c.2129T>C 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: PS4, PM2, PM3, PP1, PP3, PP5. Based on this evidence we have classified this variant as Pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV002276570 SCV002567157 pathogenic Connective tissue disorder 2021-04-01 criteria provided, single submitter clinical testing
OMIM RCV000023681 SCV000044972 pathogenic Cranioectodermal dysplasia 4 2013-08-01 no assertion criteria provided literature only
GeneReviews RCV000023681 SCV000087013 pathologic Cranioectodermal dysplasia 4 2013-09-12 no assertion criteria provided curation Converted during submission to Pathogenic.
OMIM RCV000169775 SCV000221337 pathogenic Senior-Loken syndrome 8 2013-08-01 no assertion criteria provided literature only
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356848 SCV001552119 likely pathogenic not provided no assertion criteria provided clinical testing The WDR19 p.L710S variant was identified in the literature as a homozygous variant in 2 of 151 families (freq=0.013) with autosomal recessive Retinitis Pigmentosa from Quebec but was not found in 200 French-Canadian controls (Coussa_2013_PMID:23683095). The variant was also identified in two siblings with Sensenbrenner syndrome in the compound heterozygous state with a WDR19 p.R1103* variant with the p.L710S variant inherited from the unaffected father and the p.R1103* variant inherited from the unaffected mother; neither of these variants were identified in 422 controls (Bredrup_2011_PMID:22019273). The variant was identified in dbSNP (ID: rs387906980), ClinVar (classified as pathogenic by OMIM and GeneReviews) and LOVD 3.0 (classified as likely pathogenic). The variant was identified in control databases in 3 of 249208 chromosomes at a frequency of 0.00001204 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Latino in 1 of 34514 chromosomes (freq: 0.000029) and European (non-Finnish) in 2 of 112986 chromosomes (freq: 0.000018), but was not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish), Other or South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Leu550 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.

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