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

dbSNP: rs1557083958

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255829	SCV000322477	pathogenic	not provided	2022-02-27	criteria provided, single submitter	clinical testing	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease. 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).; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26790960, 26481852, 28711740, 25533962, 28135719, 28191890, 30842224, 24621584, 23176820, 31293896, 31505688, 33504798, 33037762, 31038196)
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	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	2024-01-22	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. Variants that disrupt the donor or acceptor splice site 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, 24621584, 25744623, 26790960, 27030146, 27652284, 28554332). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with betapropeller protein-associated neurodegeneration and Rett-like syndrome with childhood iron deposition in brain (PMID: 23176820, 24621584, 28711740). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 265508). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000578469	SCV001428545	pathogenic	Neurodegeneration with brain iron accumulation 5	2023-10-13	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PM2_SUP_STR,PS4_MOD
3billion	RCV000578469	SCV002012058	pathogenic	Neurodegeneration with brain iron accumulation 5	2021-10-02	criteria provided, single submitter	clinical testing	Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 28711740, 24621584, PS4_M).It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Revvity Omics, Revvity	RCV000578469	SCV002020899	pathogenic	Neurodegeneration with brain iron accumulation 5	2021-02-24	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000578469	SCV002499092	pathogenic	Neurodegeneration with brain iron accumulation 5	2022-03-02	criteria provided, single submitter	clinical testing	PVS1, PS2_Very Strong, PM2
CeGaT Center for Human Genetics Tuebingen	RCV000255829	SCV002822025	pathogenic	not provided	2022-11-01	criteria provided, single submitter	clinical testing	WDR45: PVS1, PS2, PM2
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.
Pediatric Genetics Clinic, Sheba Medical Center	RCV000578469	SCV001712253	pathogenic	Neurodegeneration with brain iron accumulation 5	2021-05-13	no assertion criteria provided	clinical testing
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV000578469	SCV002097051	pathogenic	Neurodegeneration with brain iron accumulation 5		no assertion criteria provided	clinical testing