ClinVar Miner

Submissions for variant NM_001006657.2(WDR35):c.1922T>G (p.Leu641Ter) (rs199952377)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000288028 SCV000426023 likely pathogenic WDR35-Related Disorders 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.
Invitae RCV000648351 SCV000770167 pathogenic Cranioectodermal dysplasia 2; Short rib polydactyly syndrome 5 2018-06-19 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. This variant is present in population databases (rs199952377, ExAC 0.04%). This variant has been reported in individuals affected with cranioectodermal dysplasia, also known as Sensenbrenner syndrome (PMID: 22486404, 25914204, 28332779). ClinVar contains an entry for this variant (Variation ID: 65619). Loss-of-function variants in WDR35 are known to be pathogenic (PMID: 21473986, 25908617). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare 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,; 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.
GeneReviews RCV000055830 SCV000086816 pathologic Cranioectodermal dysplasia 2 2013-09-12 no assertion criteria provided curation Converted during submission to 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

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