ClinVar Genomic variation as it relates to human health
NM_001399.5(EDA):c.866G>A (p.Arg289His)
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_001399.5(EDA):c.866G>A (p.Arg289His)
Variation ID: 228257 Accession: VCV000228257.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq13.1 X: 70033470 (GRCh38) [ NCBI UCSC ] X: 69253320 (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 May 29, 2016 Apr 15, 2024 Jan 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001399.5:c.866G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001390.1:p.Arg289His missense NM_001005609.2:c.866G>A NP_001005609.1:p.Arg289His missense NM_001005612.3:c.857G>A NP_001005612.2:p.Arg286His missense NC_000023.11:g.70033470G>A NC_000023.10:g.69253320G>A NG_009809.2:g.422404G>A - Protein change
- R289H, R286H
- Other names
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- Canonical SPDI
- NC_000023.11:70033469: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.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
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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EDA | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
572 | 710 |
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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Likely pathogenic (1) |
criteria provided, single submitter
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Oct 11, 2015 | RCV000223248.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 9, 2023 | RCV001054886.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 1, 2020 | RCV001248822.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 20, 2023 | RCV003317157.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 1, 2024 | RCV003886387.2 |
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
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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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Likely pathogenic
(Oct 11, 2015)
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criteria provided, single submitter
Method: clinical testing
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Partial congenital absence of teeth
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000271219.2
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
Comment:
The p.Arg289His variant in EDA has been reported in one individual with non-synd romic oligodontia and segregated with disease in one sibling (Heiland 2014, conf … (more)
The p.Arg289His variant in EDA has been reported in one individual with non-synd romic oligodontia and segregated with disease in one sibling (Heiland 2014, conf erence abstract). The variant was absent from large population studies. Computat ional prediction tools and conservation analysis suggest that the p.Arg289His va riant may impact the protein. In additon, two other missense variants at the sam e amino acid position (p.Arg289Cys, p.Arg289Leu) have been reported in individua ls with non-syndromic oligodontia (Song 2009, Lee 2014), suggesting that variati on at this position is not tolerated. In summary, although additional studies ar e required to fully establish its clinical significance, the p.Arg289His variant is likely pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jun 01, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hypohidrotic X-linked ectodermal dysplasia
Tooth agenesis, selective, X-linked, 1 (X-linked inheritance)
Affected status: yes
Allele origin:
germline
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Biotechnology Lab, Dept of Biomolecular Sciences, University of Urbino
Additional submitter:
Coordinamento Interdipartimentale Malattie Rare, Azienda Ospedaliero Universitaria Ospedali Riuniti di Ancona
Accession: SCV001366090.1
First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020 |
Comment:
The Arg289His variant in EDA has been reported in one Italian family with X-linked dominant tooth agenesis, segregated with the disease in affected relatives (present … (more)
The Arg289His variant in EDA has been reported in one Italian family with X-linked dominant tooth agenesis, segregated with the disease in affected relatives (present study), and was absent from large population studies. Additionally, the same variant causes X-linked recessive hypohidrotic ectodermal dysplasia in hemizygous males within the same family. Furthermore, this variant has been described to segregate with non-syndromic oligodontia and ectodermal dysplasia in families (PMID: 26753551, Invitae). Two other missense variants affecting the same amino acidic residue Arg289 (c.865C>T p.Arg289Cys, c.866G>T p.Arg289Leu), but causing different amino acid substitutions, has been reported to be pathogenic and associated to non-syndromic oligodontia (PMID: 19278982, 24487376). In summary, the Arg289His variant meets our criteria to be classified as pathogenic. (less)
Clinical Features:
Conical tooth (present) , Partial congenital absence of teeth (present) , Dry skin (present) , Brittle hair (present)
Age: 0-9 years
Sex: male
Geographic origin: Italy
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Pathogenic
(Jun 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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Anhidrotic ectodermal dysplasia
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004020839.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
Variant summary: EDA c.866G>A (p.Arg289His) results in a non-conservative amino acid change located in the Tumor necrosis factor domain (IPR006052) of the encoded protein sequence. … (more)
Variant summary: EDA c.866G>A (p.Arg289His) results in a non-conservative amino acid change located in the Tumor necrosis factor domain (IPR006052) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183333 control chromosomes in gnomAD. c.866G>A has been reported in the literature in multiple hemizygous individuals affected with features of Hypohidrotic Ectodermal Dysplasia (with dental anomalies being the main symptoms) and has been observed to co-segregate with disease within families (example: Ruiz-Heiland_2016, Andreoni_2021, Zhang _2021, Biedziak_2022). Some female carriers have been reported with mild features of tooth agenesis, while others were unaffected (example: Ruiz-Heiland_2016, Andreoni_2021, Zhang _2021). Additionally, at least one variant at the Arg289 residue has been reported as associated with disease (p.Arg289Cys), suggesting that this codon is functionally important. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33205897, 36294409, 26753551, 33943035). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and all submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jun 09, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hypohidrotic X-linked ectodermal dysplasia
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001219244.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg289 amino acid residue in EDA. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg289 amino acid residue in EDA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19278982, 24487376, 27144394). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt EDA protein function. ClinVar contains an entry for this variant (Variation ID: 228257). This missense change has been observed in individual(s) with ectodermal dysplasia (PMID: 26753551; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 289 of the EDA protein (p.Arg289His). (less)
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Pathogenic
(Jan 01, 2024)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004702241.2
First in ClinVar: Mar 10, 2024 Last updated: Apr 15, 2024 |
Comment:
EDA: PP1:Strong, PM1, PM2, PM5, PP3, PP4
Number of individuals with the variant: 1
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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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Novel Candidate Genes for Non-Syndromic Tooth Agenesis Identified Using Targeted Next-Generation Sequencing. | Biedziak B | Journal of clinical medicine | 2022 | PMID: 36294409 |
A novel EDAR missense mutation identified by whole-exome sequencing with non-syndromic tooth agenesis in a Chinese family. | Zhang H | Molecular genetics & genomic medicine | 2021 | PMID: 33943035 |
Missense mutations in EDA and EDAR genes cause dominant syndromic tooth agenesis. | Andreoni F | Molecular genetics & genomic medicine | 2021 | PMID: 33205897 |
Functional Study of Ectodysplasin-A Mutations Causing Non-Syndromic Tooth Agenesis. | Shen W | PloS one | 2016 | PMID: 27144394 |
Oligodontia and curly hair occur with ectodysplasin-a mutations. | Lee KE | Journal of dental research | 2014 | PMID: 24487376 |
EDA gene mutations underlie non-syndromic oligodontia. | Song S | Journal of dental research | 2009 | PMID: 19278982 |
Text-mined citations for rs876657641 ...
HelpRecord last updated Apr 15, 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.