ClinVar Miner

Submissions for variant NM_001029896.2(WDR45):c.827+1G>A (rs1557083958)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255829 SCV000322477 pathogenic not provided 2018-05-18 criteria provided, single submitter clinical testing The c.830+1G>A pathogenic variant in the WDR45 gene has been reported previously in association with neurodegeneration with brain iron accumulation (Haack et al., 2012) and in an individual with clinical features of Rett syndrome who also had brain iron deposition (Ohba et al., 2014). This splice site variant destroys the canonical splice donor site in intron 10. The variant results in aberrant splicing in which 82 bp intronic sequences are retained through the use of a cryptic splice donor site within intron 10, resulting in a premature stop codon (Ohba et al., 2014). The c.830+1G>A variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.830+1G>A as a pathogenic variant.
GenomeConnect, ClinGen RCV000845069 SCV000986910 not provided Neurodegeneration with brain iron accumulation no assertion provided phenotyping only Variant interpretted as pathogenic and reported on 04/11/2016 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Institute of Human Genetics,Klinikum rechts der Isar RCV000578469 SCV000680434 pathogenic Neurodegeneration with brain iron accumulation 5 2017-10-13 criteria provided, single submitter clinical testing
Invitae RCV000578469 SCV000817297 pathogenic Neurodegeneration with brain iron accumulation 5 2018-10-29 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 10 of the WDR45 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in individuals affected with betapropeller protein-associated neurodegeneration and Rett-like syndrome with childhood iron deposition in brain (PMID: 23176820, 28711740, 24621584). ClinVar contains an entry for this variant (Variation ID: 265508). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in WDR45 are known to be pathogenic (PMID: 23176820, 24368176, 25744623). For these reasons, this variant has been classified as Pathogenic.

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