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

gnomAD frequency: 0.00003  dbSNP: rs387906980

Total submissions: 11

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	2023-10-29	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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on WDR19 protein function. 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
GeneDx	RCV001356848	SCV003915021	pathogenic	not provided	2023-04-02	criteria provided, single submitter	clinical testing	Published functional studies demonstrate the L710S variant alters subcomplex interaction, demonstrating a damaging effect (Ishida et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27241786, 28559085, 31589614, 23683095, 33517396, 22019273)
Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel	RCV003324499	SCV004030350	pathogenic	Renal dysplasia and retinal aplasia	2023-07-24	criteria provided, single submitter	research	Clinical significance based on ACMG v2.0
PreventionGenetics, part of Exact Sciences	RCV003398565	SCV004119927	pathogenic	WDR19-related condition	2023-07-09	criteria provided, single submitter	clinical testing	The WDR19 c.2129T>C variant is predicted to result in the amino acid substitution p.Leu710Ser. This variant together with another truncating variant has been reported in a patient with syndromic early childhood onset retinal dystrophy (Stone et al. 2017. PubMed ID: 28559085, Supplemental Table S1). In addition, this variant in the compound heterozygous state with another protein truncating variant has been reported in patients with cranioectodermal dysplasia (Sensenbrenner syndrome) (Daoud et al. 2016. PubMed ID: 27241786; Bredrup et al. 2011. PubMed ID: 22019273). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-39233563-T-C). This variant is interpreted as pathogenic.
OMIM	RCV000023681	SCV000044972	pathogenic	Cranioectodermal dysplasia 4	2013-08-01	no assertion criteria provided	literature only
GeneReviews	RCV000023681	SCV000087013	not provided	Cranioectodermal dysplasia 4		no assertion provided	literature only
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.