VCV000981409.9 - ClinVar

NM_001029896.2(WDR45):c.1A>G (p.Met1Val)

Germline

Classification

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.

(3)

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.

Conflicting classifications of pathogenicity
Pathogenic(2); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001029896.2(WDR45):c.1A>G (p.Met1Val)

Variation ID: 981409 Accession: VCV000981409.9

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xp11.23 X: 49078095 (GRCh38) [ NCBI UCSC ] X: 48935754 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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, 2020	Nov 17, 2024	May 6, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001029896.2:c.1A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001025067.1:p.Met1Val	missense initiator codon variant
NM_007075.4:c.1A>G	NP_009006.2:p.Met1Val	missense initiator codon variant
NC_000023.11:g.49078095T>C
NC_000023.10:g.48935754T>C
NG_033004.2:g.28076A>G

... more HGVS ... less HGVS

Protein change

M1V

Other names

Canonical SPDI

NC_000023.11:49078094:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

dbSNP: rs2065048490 VarSome

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
Gene	OMIM	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
LOC126863256	-	-	-	GRCh38 GRCh38	-	199

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.
Intellectual disability	Uncertain significance (1)	criteria provided, single submitter	Sep 10, 2020	RCV001260829.2
Neurodegeneration with brain iron accumulation 5	Pathogenic (1)	criteria provided, single submitter	Apr 28, 2021	RCV001879996.8
not provided	Pathogenic (1)	criteria provided, single submitter	May 6, 2024	RCV004783938.1

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.
Uncertain significance (Sep 10, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability Affected status: yes Allele origin: maternal	Diagnostic Laboratory, Strasbourg University Hospital Accession: SCV001437925.2 First in ClinVar: Oct 10, 2020 Last updated: Sep 03, 2023	Method: targeted next-gen sequencing
Pathogenic (Apr 28, 2021)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Neurodegeneration with brain iron accumulation 5 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002242075.4 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 25533962‚ 23687123‚ 32387008 Comment: For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this … (more) For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Disruption of the initiator codon ‚Äãhas been observed in individual(s) with clinical features of WDR45-related conditions (PMID: 25533962, 23687123, 32387008). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 981409) This variant is not present in population databases (ExAC no frequency). This sequence change affects the initiator methionine of the WDR45 mRNA. The next in-frame methionine is located at codon 25. (less)
Pathogenic (May 06, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005396383.1 First in ClinVar: Nov 17, 2024 Last updated: Nov 17, 2024	Comment: Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population … (more) Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30713886, 29981852, 23687123) (less)

Comment:

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Disruption of the initiator codon ‚Äãhas been observed in individual(s) with clinical features of WDR45-related conditions (PMID: 25533962, 23687123, 32387008). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 981409) This variant is not present in population databases (ExAC no frequency). This sequence change affects the initiator methionine of the WDR45 mRNA. The next in-frame methionine is located at codon 25.

Comment:

Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30713886, 29981852, 23687123)

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Phenotypic and Imaging Spectrum Associated With WDR45.	Adang LA	Pediatric neurology	2020	PMID: 32387008
Large-scale discovery of novel genetic causes of developmental disorders.	Deciphering Developmental Disorders Study	Nature	2015	PMID: 25533962
β-Propeller protein-associated neurodegeneration: a new X-linked dominant disorder with brain iron accumulation.	Hayflick SJ	Brain : a journal of neurology	2013	PMID: 23687123

Text-mined citations for rs2065048490 ...

These 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 19, 2024

ClinVar Genomic variation as it relates to human health

NM_001029896.2(WDR45):c.1A>G (p.Met1Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs2065048490 ...