DNA sequence analysis of the EBF3 gene demonstrated a sequence change, c.625C>T, in exon 7 that results in an amino acid change, p.Arg209Trp. This is a novel sequence change that is not present in the population databases (ExAC, gnomAD). The p.Arg209Trp change affects a highly conserved amino acid residue located in the DNA-binding domain of the EBF3 protein where all other missense pathogenic variants have been described to date. The p.Arg209Trp substitution appears to be possibly damaging using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This variant has previously been described in two symptomatic siblings with ataxia, ID, speech delay, motor developmental delay, seizures where functional studies were performed that demonstrated a likely defect in protein function (Harms et al.,2017). This sequence change is the likely cause of this phenotype, however functional studies have not been performed to prove this conclusively.
ClinVar Genomic variation as it relates to human health
NM_001375380.1(EBF3):c.625C>T (p.Arg209Trp)
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.
(8)
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
8
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001375380.1(EBF3):c.625C>T (p.Arg209Trp)
Variation ID: 375494 Accession: VCV000375494.23
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 10q26.3 10: 129877779 (GRCh38) [ NCBI UCSC ] 10: 131676043 (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 Feb 13, 2017 Oct 20, 2024 Mar 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001375380.1:c.625C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001362309.1:p.Arg209Trp missense NM_001005463.1:c.625C>T NM_001005463.3:c.625C>T NP_001005463.1:p.Arg209Trp missense NM_001375379.1:c.625C>T NP_001362308.1:p.Arg209Trp missense NM_001375389.1:c.625C>T NP_001362318.1:p.Arg209Trp missense NM_001375390.1:c.625C>T NP_001362319.1:p.Arg209Trp missense NM_001375391.1:c.625C>T NP_001362320.1:p.Arg209Trp missense NM_001375392.1:c.625C>T NP_001362321.1:p.Arg209Trp missense NC_000010.11:g.129877779G>A NC_000010.10:g.131676043G>A NG_030038.1:g.91049C>T - Protein change
- R209W
- Other names
- -
- Canonical SPDI
- NC_000010.11:129877778:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
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. |
|||
| EBF3 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
241 | 342 | |
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 (4) |
criteria provided, single submitter
|
Apr 1, 2021 | RCV000417009.8 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Dec 28, 2016 | RCV001266965.3 | |
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 1, 2024 | RCV001821145.13 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Feb 22, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV002064338.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
DNA sequence analysis of the EBF3 gene demonstrated a sequence change, c.625C>T, in exon 7 that results in an amino acid change, p.Arg209Trp. This is … (more)
DNA sequence analysis of the EBF3 gene demonstrated a sequence change, c.625C>T, in exon 7 that results in an amino acid change, p.Arg209Trp. This is a novel sequence change that is not present in the population databases (ExAC, gnomAD). The p.Arg209Trp change affects a highly conserved amino acid residue located in the DNA-binding domain of the EBF3 protein where all other missense pathogenic variants have been described to date. The p.Arg209Trp substitution appears to be possibly damaging using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This variant has previously been described in two symptomatic siblings with ataxia, ID, speech delay, motor developmental delay, seizures where functional studies were performed that demonstrated a likely defect in protein function (Harms et al.,2017). This sequence change is the likely cause of this phenotype, however functional studies have not been performed to prove this conclusively. (less)
|
|
|
Likely pathogenic
(Dec 28, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV001445146.2
First in ClinVar: Nov 21, 2020 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: Caucasian
|
|
|
Pathogenic
(Oct 21, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002586608.2
First in ClinVar: Oct 29, 2022 Last updated: Mar 04, 2023 |
Comment:
Published functional studies suggest a damaging effect as R209W results in mislocalization of the EBF3 protein and impaired association with chromatin (Harms et al., 2016); … (more)
Published functional studies suggest a damaging effect as R209W results in mislocalization of the EBF3 protein and impaired association with chromatin (Harms et al., 2016); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34050706, 32637629, 28017373) (less)
|
|
|
Pathogenic
(Apr 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hypotonia, ataxia, and delayed development syndrome
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV003835415.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
|
|
|
Pathogenic
(Mar 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004811857.7
First in ClinVar: Apr 15, 2024 Last updated: Oct 20, 2024 |
Comment:
EBF3: PS2, PM1, PM2, PM5, PS4:Moderate, PP2
Number of individuals with the variant: 1
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Hypotonia, ataxia, and delayed development syndrome
Affected status: yes
Allele origin:
de novo
|
NEUROCHILD, Pediatric Research Center
Accession: SCV001547520.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
|
|
|
Pathogenic
(Feb 23, 2023)
|
no assertion criteria provided
Method: literature only
|
HYPOTONIA, ATAXIA, AND DELAYED DEVELOPMENT SYNDROME
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000494483.2
First in ClinVar: Feb 13, 2017 Last updated: Mar 18, 2023 |
Comment on evidence:
In 2 sibs (family 1, subjects 1 and 2) with hypotonia, ataxia, and delayed development syndrome (HADDS; 617330), Harms et al. (2017) identified a heterozygous … (more)
In 2 sibs (family 1, subjects 1 and 2) with hypotonia, ataxia, and delayed development syndrome (HADDS; 617330), Harms et al. (2017) identified a heterozygous c.625C-T transition (c.625C-T, NM_001005463.2) in exon 7 of the EBF3 gene, resulting in an arg209-to-trp (R209W) substitution at a highly conserved residue in the DNA-binding domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was found to be mosaic in the unaffected mother and absent in the unaffected sibs. It was not found in the dbSNP (build 138), 1000 Genomes Project, Exome Variant Server, or ExAC databases. In vitro functional expression studies in HEK293 cells showed that the mutant protein localized to the nucleus but with altered localization to the cytoplasm as well, decreased association with chromatin, and significantly decreased ability to activate transcription of a reporter gene compared to controls. Transcriptional activation was not significantly reduced when the mutation was coexpressed with the wildtype gene, arguing against a dominant-negative effect for this mutation. Deisseroth et al. (2022) performed a genotypic assessment of 41 patients with HADDS in their cohort and 47 previously reported patients. Nine unrelated individuals had variants affecting arg209, including R209W in 5 patients. (less)
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Hypotonia, ataxia, and delayed development syndrome
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV001737499.2
First in ClinVar: Jun 19, 2021 Last updated: Oct 01, 2022 |
Comment:
Reported in 2 unrelated persons
|
Comment:
Comment:
Published functional studies suggest a damaging effect as R209W results in mislocalization of the EBF3 protein and impaired association with chromatin (Harms et al., 2016); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34050706, 32637629, 28017373)
Comment:
EBF3: PS2, PM1, PM2, PM5, PS4:Moderate, PP2
Comment:
Reported in 2 unrelated persons
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:
DNA sequence analysis of the EBF3 gene demonstrated a sequence change, c.625C>T, in exon 7 that results in an amino acid change, p.Arg209Trp. This is a novel sequence change that is not present in the population databases (ExAC, gnomAD). The p.Arg209Trp change affects a highly conserved amino acid residue located in the DNA-binding domain of the EBF3 protein where all other missense pathogenic variants have been described to date. The p.Arg209Trp substitution appears to be possibly damaging using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This variant has previously been described in two symptomatic siblings with ataxia, ID, speech delay, motor developmental delay, seizures where functional studies were performed that demonstrated a likely defect in protein function (Harms et al.,2017). This sequence change is the likely cause of this phenotype, however functional studies have not been performed to prove this conclusively.
Comment:
Published functional studies suggest a damaging effect as R209W results in mislocalization of the EBF3 protein and impaired association with chromatin (Harms et al., 2016); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34050706, 32637629, 28017373)
Comment:
EBF3: PS2, PM1, PM2, PM5, PS4:Moderate, PP2
Comment:
Reported in 2 unrelated persons
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| An Integrated Phenotypic and Genotypic Approach Reveals a High-Risk Subtype Association for EBF3 Missense Variants Affecting the Zinc Finger Domain. | Deisseroth CA | Annals of neurology | 2022 | PMID: 35340043 |
| Genetic background of ataxia in children younger than 5 years in Finland. | Ignatius E | Neurology. Genetics | 2020 | PMID: 32637629 |
| Mutations in EBF3 Disturb Transcriptional Profiles and Cause Intellectual Disability, Ataxia, and Facial Dysmorphism. | Harms FL | American journal of human genetics | 2017 | PMID: 28017373 |
Text-mined citations for rs779003155 ...
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.