Submissions for variant NM_020779.4(WDR35):c.1889T>G (p.Leu630Ter)

gnomAD frequency: 0.00019  dbSNP: rs199952377

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000288028	SCV000426023	likely pathogenic	WDR35-related disorder	2017-04-27	criteria provided, single submitter	clinical testing	The WDR35 c.1922T>G (p.Leu641Ter) variant is a stop-gained variant that has been reported in two studies in which it was found in two individuals with cranioectodermal dysplasia, both in a compound heterozygous state with a missense variant (Hoffer et al. 2013; Li et al. 2015). The variant was absent from 300 control chromosomes but is reported at a frequency of 0.00039 in the European (non-Finnish) population of the Exome Aggregation Consortium. Due to the potential impact of stop-gained variants and the supporting evidence, the p.Leu641Ter variant is classified as likely pathogenic for WDR35-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000648351	SCV000770167	pathogenic	Cranioectodermal dysplasia 2; Short-rib thoracic dysplasia 7 with or without polydactyly	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu641*) in the WDR35 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in WDR35 are known to be pathogenic (PMID: 22486404, 29068549). This variant is present in population databases (rs199952377, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with cranioectodermal dysplasia, also known as Sensenbrenner syndrome (PMID: 22486404, 25914204, 28332779). ClinVar contains an entry for this variant (Variation ID: 65619). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000826131	SCV000967645	likely pathogenic	Cranioectodermal dysplasia	2018-03-12	criteria provided, single submitter	clinical testing	The p.Leu641X variant in WDR35 has been reported in 3 compound heterozygous indi viduals with cranioectodermal dysplasia (Hoffer 2013, Li 2015, Walczak-Sztulpa 2 017) and has been reported in ClinVar (Variation ID #65619). This variant has al so been identified in 0.035% (37/105,800) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs19995237 7). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsens e variant leads to a premature termination codon at position 641 which is predic ted to lead to a truncated or absent protein. In summary, although additional st udies are required to fully establish its clinical significance, the p.Leu641X variant is likely pathogenic for cranioectodermal dysplasia in an autosomal rece ssive manner. ACMG/AMP Criteria applied: PVS1_Strong, PS3_Supporting, PM3_Suppor ting.
GeneDx	RCV001557398	SCV001779153	likely pathogenic	not provided	2024-06-14	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 34490615, 25914204, 28332779, 22486404, 31980526, 34426522, 31589614, 34421506, 38161384, 35875935, 29068549, 33421337, 37895316, 38792657)
Revvity Omics, Revvity	RCV001557398	SCV002020898	pathogenic	not provided	2021-10-14	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000055830	SCV004041065	pathogenic	Cranioectodermal dysplasia 2	2023-05-26	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001557398	SCV004138649	pathogenic	not provided	2022-12-01	criteria provided, single submitter	clinical testing	WDR35: PVS1, PS4:Moderate
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000288028	SCV005039172	pathogenic	WDR35-related disorder	2024-03-25	criteria provided, single submitter	clinical testing	Variant summary: WDR35 c.1922T>G (p.Leu641X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00016 in 218956 control chromosomes. c.1922T>G has been reported in the literature in individuals affected with WDR35-Related Disorders (Li_2015). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 25914204). ClinVar contains an entry for this variant (Variation ID: 65619). Based on the evidence outlined above, the variant was classified as pathogenic.
Dan Cohn Lab, University Of California Los Angeles	RCV000515864	SCV000612057	pathogenic	Jeune thoracic dystrophy	2017-06-01	no assertion criteria provided	research
OMIM	RCV000055830	SCV000680477	pathogenic	Cranioectodermal dysplasia 2	2018-03-30	no assertion criteria provided	literature only
University of Washington Center for Mendelian Genomics, University of Washington	RCV000515864	SCV001480004	likely pathogenic	Jeune thoracic dystrophy		no assertion criteria provided	research