PVS1, PS2_Very Strong, PM2
ClinVar Genomic variation as it relates to human health
NM_001029896.2(WDR45):c.827+1G>A
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(11)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
11
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001029896.2(WDR45):c.827+1G>A
Variation ID: 265508 Accession: VCV000265508.37
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xp11.23 X: 49075363 (GRCh38) [ NCBI UCSC ] X: 48933022 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 10, 2016 Oct 20, 2024 Jan 22, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001029896.2:c.827+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_007075.4:c.830+1G>A splice donor NC_000023.11:g.49075363C>T NC_000023.10:g.48933022C>T NG_033004.2:g.30808G>A - Protein change
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- Other names
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- Canonical SPDI
- NC_000023.11:49075362:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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| WDR45 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
375 | 663 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 1, 2022 | RCV000255829.19 | |
| Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Jan 22, 2024 | RCV000578469.24 | |
| not provided (1) |
no classification provided
|
- | RCV000845069.2 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Oct 13, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Neurodegeneration with brain iron accumulation 5
(X-linked inheritance)
Affected status: yes
Allele origin:
de novo
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV000680434.1
First in ClinVar: Feb 08, 2018 Last updated: Feb 08, 2018 |
Sex: male
Tissue: blood
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Pathogenic
(Mar 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Neurodegeneration with brain iron accumulation 5
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV002499092.1
First in ClinVar: Apr 16, 2022 Last updated: Apr 16, 2022 |
Comment:
PVS1, PS2_Very Strong, PM2
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Pathogenic
(Feb 27, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000322477.8
First in ClinVar: Oct 10, 2016 Last updated: Mar 04, 2023 |
Comment:
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 … (more)
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) (less)
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Pathogenic
(Nov 01, 2022)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002822025.14
First in ClinVar: Jan 21, 2023 Last updated: Oct 20, 2024 |
Comment:
WDR45: PVS1, PS2, PM2
Number of individuals with the variant: 1
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Pathogenic
(Oct 02, 2021)
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criteria provided, single submitter
Method: clinical testing
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Neurodegeneration with brain iron accumulation 5
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002012058.1
First in ClinVar: Nov 11, 2021 Last updated: Nov 11, 2021 |
Comment:
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. … (more)
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. (less)
Clinical Features:
Blindness (present) , Abnormal facial shape (present) , Delayed fine motor development (present) , Bilateral tonic-clonic seizure (present) , Delayed gross motor development (present) , … (more)
Blindness (present) , Abnormal facial shape (present) , Delayed fine motor development (present) , Bilateral tonic-clonic seizure (present) , Delayed gross motor development (present) , Intellectual disability (present) , Low-set ears (present) , Thick upper lip vermilion (present) , Delayed speech and language development (present) , Intellectual disability, mild (present) , Obesity (present) , Visual impairment (present) , Hirsutism (present) (less)
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Pathogenic
(Oct 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Neurodegeneration with brain iron accumulation 5
(X-linked dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001428545.2
First in ClinVar: Aug 15, 2020 Last updated: Nov 04, 2023 |
Comment:
Criteria applied: PVS1,PM2_SUP_STR,PS4_MOD
Clinical Features:
Intellectual disability, severe (present) , Focal-onset seizure (present)
Sex: female
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Pathogenic
(Feb 24, 2021)
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criteria provided, single submitter
Method: clinical testing
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Neurodegeneration with brain iron accumulation 5
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002020899.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
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Pathogenic
(Jan 22, 2024)
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criteria provided, single submitter
Method: clinical testing
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Neurodegeneration with brain iron accumulation 5
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000817297.5
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
|
Neurodegeneration with brain iron accumulation 5
(X-linked dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Génétique des Maladies du Développement, Hospices Civils de Lyon
Accession: SCV002097051.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
Sex: female
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Pathogenic
(May 13, 2021)
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no assertion criteria provided
Method: clinical testing
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Neurodegeneration with brain iron accumulation 5
Affected status: yes
Allele origin:
de novo
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Pediatric Genetics Clinic, Sheba Medical Center
Accession: SCV001712253.1
First in ClinVar: Dec 12, 2021 Last updated: Dec 12, 2021 |
Clinical Features:
Neurodevelopmental delay (present) , Seizure (present) , Premature closure of fontanelles (present)
Secondary finding: no
|
|
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not provided
(-)
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no classification provided
Method: phenotyping only
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Neurodegeneration with brain iron accumulation
Affected status: yes
Allele origin:
unknown
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GenomeConnect, ClinGen
Accession: SCV000986910.1
First in ClinVar: Aug 31, 2019 Last updated: Aug 31, 2019 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Abnormality of vision (present) , Myopia (present) , Abnormality of the nervous system (present) , Cognitive impairment (present) , Abnormality of coordination (present) , EEG … (more)
Abnormality of vision (present) , Myopia (present) , Abnormality of the nervous system (present) , Cognitive impairment (present) , Abnormality of coordination (present) , EEG abnormality (present) , Generalized hypotonia (present) , Parkinsonism (present) , Seizures (present) , Autistic behavior (present) , Hyperhidrosis (present) , Abnormality of muscle physiology (present) , Abnormality of the musculature of the limbs (present) , Hypercholesterolemia (present) , Feeding difficulties (present) , Abnormality of the liver (present) (less)
Age: 0-9 years
Sex: female
Testing laboratory: GeneDx
Date variant was reported to submitter: 2016-04-11
Testing laboratory interpretation: Pathogenic
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Comment:
Comment:
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)
Comment:
WDR45: PVS1, PS2, PM2
Comment:
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.
Comment:
Criteria applied: PVS1,PM2_SUP_STR,PS4_MOD
Comment:
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.
Comment:
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.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
PVS1, PS2_Very Strong, PM2
Comment:
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)
Comment:
WDR45: PVS1, PS2, PM2
Comment:
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.
Comment:
Criteria applied: PVS1,PM2_SUP_STR,PS4_MOD
Comment:
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.
Comment:
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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Early manifestations of epileptic encephalopathy, brain atrophy, and elevation of serum neuron specific enolase in a boy with beta-propeller protein-associated neurodegeneration. | Takano K | European journal of medical genetics | 2017 | PMID: 28711740 |
| Genomic diagnosis for children with intellectual disability and/or developmental delay. | Bowling KM | Genome medicine | 2017 | PMID: 28554332 |
| Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients. | de Kovel CG | Molecular genetics & genomic medicine | 2016 | PMID: 27652284 |
| WDR45 mutations in three male patients with West syndrome. | Nakashima M | Journal of human genetics | 2016 | PMID: 27030146 |
| WDR45 mutations in Rett (-like) syndrome and developmental delay: Case report and an appraisal of the literature. | Hoffjan S | Molecular and cellular probes | 2016 | PMID: 26790960 |
| High frequency of beta-propeller protein-associated neurodegeneration (BPAN) among patients with intellectual disability and young-onset parkinsonism. | Nishioka K | Neurobiology of aging | 2015 | PMID: 25744623 |
| De novo WDR45 mutation in a patient showing clinically Rett syndrome with childhood iron deposition in brain. | Ohba C | Journal of human genetics | 2014 | PMID: 24621584 |
| Beta-propeller protein-associated neurodegeneration (BPAN), a rare form of NBIA: novel mutations and neuropsychiatric phenotype in three adult patients. | Verhoeven WM | Parkinsonism & related disorders | 2014 | PMID: 24368176 |
| Exome sequencing reveals de novo WDR45 mutations causing a phenotypically distinct, X-linked dominant form of NBIA. | Haack TB | American journal of human genetics | 2012 | PMID: 23176820 |
| Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
Text-mined citations for rs1557083958 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.