Not observed in large population cohorts (gnomAD); In-frame deletion of 1 amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24368176, 26577041, 28371320, 26633542, 29445477)
ClinVar Genomic variation as it relates to human health
NM_001029896.2(WDR45):c.746CCT[1] (p.Ser250del)
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.
(7)
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/Likely pathogenic
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001029896.2(WDR45):c.746CCT[1] (p.Ser250del)
Variation ID: 418542 Accession: VCV000418542.17
- Type and length
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Microsatellite, 3 bp
- Location
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Cytogenetic: Xp11.23 X: 49075440-49075442 (GRCh38) [ NCBI UCSC ] X: 48933099-48933101 (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 Apr 27, 2017 Nov 24, 2024 Oct 8, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001029896.2:c.746CCT[1] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001025067.1:p.Ser250del inframe deletion NM_001029896.2:c.749_751del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_007075.3:c.752_754delCCT NM_007075.4:c.749CCT[1] NP_009006.2:p.Ser251del inframe deletion NC_000023.11:g.49075442GAG[1] NC_000023.10:g.48933101GAG[1] NG_033004.2:g.30726CCT[1] - Protein change
- S251del, S250del
- Other names
- -
- Canonical SPDI
- NC_000023.11:49075439:AGGAGGAG:AGGAG
-
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.
- -
- 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. |
|||
| 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 (1) |
criteria provided, single submitter
|
Sep 4, 2022 | RCV000486845.4 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Mar 9, 2018 | RCV001266673.2 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Oct 8, 2024 | RCV001242357.13 |
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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|---|---|---|---|---|---|
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Pathogenic
(May 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Neurodegeneration with brain iron accumulation 5
Affected status: unknown
Allele origin:
germline
|
Mendelics
Accession: SCV002519971.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
|
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Likely pathogenic
(Mar 09, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV001444850.2
First in ClinVar: Nov 21, 2020 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Seizures (present) , Absence seizures (present) , Carious teeth (present) , Nuchal cord (present) , Pineal cyst (present) , Macule (present) , Homonymous hemianopia (present) … (more)
Seizures (present) , Absence seizures (present) , Carious teeth (present) , Nuchal cord (present) , Pineal cyst (present) , Macule (present) , Homonymous hemianopia (present) , Glandular hypospadias (present) , Hemianopia (present) , Inversion of nipple (present) , Insomnia (present) , Toe walking (present) , Round face (present) , Exotropia (present) , Pointed chin (present) , Drooling (present) , Broad forehead (present) , Hypospadias, penile (present) , Short neck (present) , Cerebral atrophy (present) , Constipation (present) , Pectus excavatum (present) , Spasticity (present) , Feeding difficulties (present) , Failure to thrive (present) , Optic atrophy (present) , Hypertelorism (present) , Microcephaly (present) , Global developmental delay (present) , Broad-based gait (present) , Short stature (present) , Intellectual disability (present) , Autistic behavior (present) , Protruding ear (present) , Midface retrusion (present) , Low-set ears (present) , Epicanthus (present) , Muscular hypotonia (present) , Behavioral abnormality (present) , Self-injurious behavior (present) , Recurrent otitis media (present) (less)
Sex: male
Ethnicity/Population group: Caucasian
|
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Pathogenic
(Sep 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000565661.6
First in ClinVar: Apr 27, 2017 Last updated: Mar 04, 2023 |
Comment:
Not observed in large population cohorts (gnomAD); In-frame deletion of 1 amino acids in a non-repeat region; In silico analysis supports a deleterious effect on … (more)
Not observed in large population cohorts (gnomAD); In-frame deletion of 1 amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24368176, 26577041, 28371320, 26633542, 29445477) (less)
|
|
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Pathogenic
(Jun 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Neurodegeneration with brain iron accumulation 5
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001415439.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 418542). This variant has been observed … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 418542). This variant has been observed in individual(s) with neurodegeneration with brain iron accumulation (PMID: 24368176, 28371320). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This variant, c.752_754del, results in the deletion of 1 amino acid(s) of the WDR45 protein (p.Ser251del), but otherwise preserves the integrity of the reading frame. (less)
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|
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Pathogenic
(Oct 08, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Neurodegeneration with brain iron accumulation 5
(X-linked dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV005398344.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neurodegeneration with brain iron accumulation 5 (MIM#300894). (I) 0110 - This gene is associated with X-linked dominant disease. (I) 0213 - In-frame insertion/deletion in a non-repetitive region that has high conservation. (SP) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0600 - Variant is located in the annotated proppin repeat (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as likely pathogenic and pathogenic (ClinVar), and observed as heterozygous and hemizygous in multiple affected individuals (PMID: 28371320; PMID: 24368176; DECIPHER). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
|
|
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Pathogenic
(Oct 08, 2019)
|
no assertion criteria provided
Method: clinical testing
|
Neurodegeneration with brain iron accumulation 5
(X-linked inheritance)
Affected status: yes
Allele origin:
germline
|
Clinical Genomics Laboratory, Stanford Medicine
Accession: SCV001427088.1
First in ClinVar: Aug 16, 2020 Last updated: Aug 16, 2020 |
Comment:
The p.Ser251del variant in the WDR45 gene has been previously reported in 5 unrelated individuals with BPAN or WDR45-associated clinical features (Verhoeven et al., 2014; … (more)
The p.Ser251del variant in the WDR45 gene has been previously reported in 5 unrelated individuals with BPAN or WDR45-associated clinical features (Verhoeven et al., 2014; Redon et al., 2017; ClinVar Accession VCV000418542.2; GeneDx, personal communication, October 3, 2019). In three of these reported individuals, the p.Ser251del variant occurred de novo. This variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). The p.Ser251del variant results in an in-frame deletion of 1 amino acid, and computational tools predict that this variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Ser251del variant as pathogenic for X-linked Beta-propeller protein-associated neurodegeneration based on the information above. [ACMG evidence codes used: PS2_VeryStrong; PM2; PP3] (less)
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|
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Likely pathogenic
(Jun 01, 2022)
|
no assertion criteria provided
Method: provider interpretation
|
Neurodegeneration with brain iron accumulation 5
Affected status: yes
Allele origin:
inherited
|
Solve-RD Consortium
Accession: SCV005200075.1
First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024
Comment:
Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and … (more)
Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. (less)
|
Comment:
Variant confirmed as disease-causing by referring clinical team
|
Comment:
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 418542). This variant has been observed in individual(s) with neurodegeneration with brain iron accumulation (PMID: 24368176, 28371320). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This variant, c.752_754del, results in the deletion of 1 amino acid(s) of the WDR45 protein (p.Ser251del), but otherwise preserves the integrity of the reading frame.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neurodegeneration with brain iron accumulation 5 (MIM#300894). (I) 0110 - This gene is associated with X-linked dominant disease. (I) 0213 - In-frame insertion/deletion in a non-repetitive region that has high conservation. (SP) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0600 - Variant is located in the annotated proppin repeat (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as likely pathogenic and pathogenic (ClinVar), and observed as heterozygous and hemizygous in multiple affected individuals (PMID: 28371320; PMID: 24368176; DECIPHER). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
The p.Ser251del variant in the WDR45 gene has been previously reported in 5 unrelated individuals with BPAN or WDR45-associated clinical features (Verhoeven et al., 2014; Redon et al., 2017; ClinVar Accession VCV000418542.2; GeneDx, personal communication, October 3, 2019). In three of these reported individuals, the p.Ser251del variant occurred de novo. This variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). The p.Ser251del variant results in an in-frame deletion of 1 amino acid, and computational tools predict that this variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Ser251del variant as pathogenic for X-linked Beta-propeller protein-associated neurodegeneration based on the information above. [ACMG evidence codes used: PS2_VeryStrong; PM2; PP3]
Comment:
Variant confirmed as disease-causing by referring clinical team
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:
Not observed in large population cohorts (gnomAD); In-frame deletion of 1 amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24368176, 26577041, 28371320, 26633542, 29445477)
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 418542). This variant has been observed in individual(s) with neurodegeneration with brain iron accumulation (PMID: 24368176, 28371320). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This variant, c.752_754del, results in the deletion of 1 amino acid(s) of the WDR45 protein (p.Ser251del), but otherwise preserves the integrity of the reading frame.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neurodegeneration with brain iron accumulation 5 (MIM#300894). (I) 0110 - This gene is associated with X-linked dominant disease. (I) 0213 - In-frame insertion/deletion in a non-repetitive region that has high conservation. (SP) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0600 - Variant is located in the annotated proppin repeat (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as likely pathogenic and pathogenic (ClinVar), and observed as heterozygous and hemizygous in multiple affected individuals (PMID: 28371320; PMID: 24368176; DECIPHER). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
The p.Ser251del variant in the WDR45 gene has been previously reported in 5 unrelated individuals with BPAN or WDR45-associated clinical features (Verhoeven et al., 2014; Redon et al., 2017; ClinVar Accession VCV000418542.2; GeneDx, personal communication, October 3, 2019). In three of these reported individuals, the p.Ser251del variant occurred de novo. This variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). The p.Ser251del variant results in an in-frame deletion of 1 amino acid, and computational tools predict that this variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Ser251del variant as pathogenic for X-linked Beta-propeller protein-associated neurodegeneration based on the information above. [ACMG evidence codes used: PS2_VeryStrong; PM2; PP3]
Comment:
Variant confirmed as disease-causing by referring clinical team
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Intragenic deletion of the WDR45 gene in a male with encephalopathy, severe psychomotor disability, and epilepsy. | Redon S | American journal of medical genetics. Part A | 2017 | PMID: 28371320 |
| 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 |
Text-mined citations for rs1064793294 ...
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 Nov 25, 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.