ClinVar Genomic variation as it relates to human health
NM_003931.3(WASF1):c.1516C>T (p.Arg506Ter)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_003931.3(WASF1):c.1516C>T (p.Arg506Ter)
Variation ID: 561980 Accession: VCV000561980.35
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6q21 6: 110101594 (GRCh38) [ NCBI UCSC ] 6: 110422797 (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 Sep 22, 2018 Jul 16, 2023 Mar 26, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003931.3:c.1516C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003922.1:p.Arg506Ter nonsense NM_001024934.2:c.1516C>T NP_001020105.1:p.Arg506Ter nonsense NM_001024935.2:c.1516C>T NP_001020106.1:p.Arg506Ter nonsense NM_001024936.2:c.1516C>T NP_001020107.1:p.Arg506Ter nonsense NC_000006.12:g.110101594G>A NC_000006.11:g.110422797G>A - Protein change
- R506*
- Other names
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- Canonical SPDI
- NC_000006.12:110101593:G:A
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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
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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WASF1 | - | - |
GRCh38 GRCh37 |
58 | 85 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
no assertion criteria provided
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Jan 1, 2018 | RCV000681442.2 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Mar 26, 2023 | RCV000984536.9 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 9, 2022 | RCV001731882.6 |
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
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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
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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
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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
(Sep 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Neurodevelopmental disorder with absent language and variable seizures
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002558043.2
First in ClinVar: Aug 08, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease … (more)
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0205 - Variant is predicted to result in a truncated protein with less than 1/3 of the protein affected (exon 10 of 11). (P) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (SP) 0703 - Comparable variants have moderate previous evidence for pathogenicity. Two other variants predicted to cause a truncated protein have been reported as pathogenic (ClinVar, PMID: 29961568). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported in patients with intellectual disability (ClinVar, PMID: 29961568). (SP) 0905 - No segregation evidence has been identified for this variant. (N) 1001 - Strong functional evidence supporting abnormal protein function. Functional studies using fibroblast cells from two affected individuals showed a truncated WASF1 and a defect in actin remodeling (PMID: 29961568). (P) 1204 - Variant shown to be de novo in proband (parental status not tested but assumed). (P) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign (less)
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Pathogenic
(Jan 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Neurodevelopmental disorder with absent language and variable seizures
Affected status: yes
Allele origin:
de novo
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Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV003804258.1
First in ClinVar: Feb 25, 2023 Last updated: Feb 25, 2023 |
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Pathogenic
(Mar 09, 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: SCV001982562.3
First in ClinVar: Oct 30, 2021 Last updated: Mar 04, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is not a known mechanism of disease; Not observed in large … (more)
Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is not a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29961568, 34845217, 34356165) (less)
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Pathogenic
(Mar 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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Neurodevelopmental disorder with absent language and variable seizures
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003922911.1
First in ClinVar: May 13, 2023 Last updated: May 13, 2023 |
Comment:
Variant summary: WASF1 c.1516C>T (p.Arg506X) results in a premature termination codon that has been reported to result in a truncation of the encoded protein (Ito_2018) … (more)
Variant summary: WASF1 c.1516C>T (p.Arg506X) results in a premature termination codon that has been reported to result in a truncation of the encoded protein (Ito_2018) and predicted to disrupt the C-terminal actin binding WCA domain. The variant was absent in 247760 control chromosomes. c.1516C>T has been reported in the literature as a recurrent de-novo variant in individuals affected with features of Neurodevelopmental Disorder With Absent Language And Variable Seizures (example, Ito_2018, Srivastava_2021, Shimojima_2021). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function reporting a defect in actin remodeling (Ito_2018). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Nov 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002009994.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
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Pathogenic
(Jan 01, 2018)
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no assertion criteria provided
Method: research
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Intellectual disability
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV000808905.1
First in ClinVar: Sep 22, 2018 Last updated: Sep 22, 2018 |
Observation 1: Observation 2:
Family history: no
Sex: male
Observation 3:
Family history: no
Sex: male
Observation 4:
Family history: no
Sex: male
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Pathogenic
(Dec 20, 2019)
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no assertion criteria provided
Method: literature only
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NEURODEVELOPMENTAL DISORDER WITH ABSENT LANGUAGE AND VARIABLE SEIZURES
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV001132595.1
First in ClinVar: Dec 31, 2019 Last updated: Dec 31, 2019 |
Comment on evidence:
In 3 unrelated adult patients (P1, P2, and P5) with neurodevelopmental disorder with absent language and variable seizures (NEDALVS; 618707), Ito et al. (2018) identified … (more)
In 3 unrelated adult patients (P1, P2, and P5) with neurodevelopmental disorder with absent language and variable seizures (NEDALVS; 618707), Ito et al. (2018) identified a de novo heterozygous c.1516C-T transition (c.1516C-T, NM_003931.2) in exon 9 of the WASF1 gene, resulting in an arg506-to-ter (R506X) substitution within the WH2 domain of the highly conserved C-terminal WCA domain. The mutation, which was found by trio-based exome sequencing and confirmed by Sanger sequencing, was not found in the 1000 Genomes Project, ExAC, or gnomAD databases. Patient 1 had de novo variants in 3 other genes, but these were determined as unlikely to be responsible for the phenotype. Western blot analysis of fibroblasts from P1 and P2 showed about 50% residual wildtype protein and 14 to 25% presence of an approximately 70-kD truncated protein, suggesting that some of the truncated protein was expressed, although being unstable at either the mRNA or protein levels. The truncated variant was not found in control cells. Patient cells showed abnormal lamellipodia formation at the cell periphery and defective actin remodeling, as well as elongated mitochondria, compared to controls, suggesting altered actin polymerization and defects in the normal mitochondrial fission/fusion balance. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Neurodevelopmental disorder with absent language and variable seizures
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Department of Rehabilitation, Children’s Hospital of Chongqing Medical University
Accession: SCV002761343.1
First in ClinVar: Jun 17, 2023 Last updated: Jun 17, 2023 |
Observation 1:
Age: 0-9 years
Sex: female
Observation 2:
Age: 0-9 years
Sex: female
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Recurrent de novo pathogenic variant of WASF1 in a Japanese patient with neurodevelopmental disorder with absent language and variable seizures. | Shimojima Yamamoto K | Human genome variation | 2021 | PMID: 34845217 |
Expansion of the Genotypic and Phenotypic Spectrum of WASF1-Related Neurodevelopmental Disorder. | Srivastava S | Brain sciences | 2021 | PMID: 34356165 |
De Novo Truncating Mutations in WASF1 Cause Intellectual Disability with Seizures. | Ito Y | American journal of human genetics | 2018 | PMID: 29961568 |
Text-mined citations for rs1562159562 ...
HelpRecord last updated Sep 30, 2023
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.