ClinVar Genomic variation as it relates to human health
NM_022336.4(EDAR):c.1259G>A (p.Arg420Gln)
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_022336.4(EDAR):c.1259G>A (p.Arg420Gln)
Variation ID: 5853 Accession: VCV000005853.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q13 2: 108896995 (GRCh38) [ NCBI UCSC ] 2: 109513451 (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 Aug 22, 2016 Oct 8, 2024 Sep 20, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_022336.4:c.1259G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_071731.1:p.Arg420Gln missense NC_000002.12:g.108896995C>T NC_000002.11:g.109513451C>T NG_008257.1:g.97378G>A Q9UNE0:p.Arg420Gln - Protein change
- R420Q
- Other names
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- Canonical SPDI
- NC_000002.12:108896994:C:T
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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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Trans-Omics for Precision Medicine (TOPMed) 0.00000
- Links
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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EDAR | - | - |
GRCh38 GRCh37 |
3 | 387 | |
RANBP2 | - | - |
GRCh38 GRCh37 |
1036 | 1637 |
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
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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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Aug 1, 1999 | RCV000006211.5 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 20, 2024 | RCV000255701.6 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Oct 10, 2022 | RCV000755721.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 8, 2023 | RCV001050412.6 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 25, 2018 | RCV001334149.1 |
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
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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
(Apr 19, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000225690.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 3
Sex: mixed
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Pathogenic
(Oct 15, 2018)
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criteria provided, single submitter
Method: curation
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Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant
Affected status: unknown
Allele origin:
unknown
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SIB Swiss Institute of Bioinformatics
Accession: SCV000883203.1
First in ClinVar: Feb 18, 2019 Last updated: Feb 18, 2019 |
Comment:
This variant is interpreted as Pathogenic, for Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant. The following ACMG Tag(s) were applied: PM2 => Absent from controls … (more)
This variant is interpreted as Pathogenic, for Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PM6 => Assumed de novo, but without confirmation of paternity and maternity (https://www.ncbi.nlm.nih.gov/pubmed/16435307). PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (https://www.ncbi.nlm.nih.gov/pubmed/18231121) (https://www.ncbi.nlm.nih.gov/pubmed/10431241). PM1 => Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation (http://www.uniprot.org/uniprot/Q9UNE0). PS3 => Well-established functional studies show a deleterious effect (https://www.ncbi.nlm.nih.gov/pubmed/11035039). (less)
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Likely pathogenic
(Jan 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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ECTODERMAL DYSPLASIA ANHIDROTIC 03
Affected status: yes
Allele origin:
unknown
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Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000923715.1
First in ClinVar: Jun 17, 2019 Last updated: Jun 17, 2019 |
Number of individuals with the variant: 1
Geographic origin: Iran
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Likely pathogenic
(Jan 25, 2018)
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criteria provided, single submitter
Method: clinical testing
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Ectodermal dysplasia 11B, hypohidrotic/hair/tooth type, autosomal recessive
Affected status: yes
Allele origin:
de novo
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Baylor Genetics
Accession: SCV001526904.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been reported in a family with autosomal dominant … (more)
This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been reported in a family with autosomal dominant hypohidrotic ectodermal dysplasia [PMID: 10431241] and was shown to decrease the EDAR protein's ability to repress the Lef-1/b-catenin activity in vitro [PMID: 15013427] (less)
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Pathogenic
(Mar 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant
Autosomal recessive hypohidrotic ectodermal dysplasia syndrome
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001214517.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects EDAR function (PMID: 11035039, 15013427). Advanced … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects EDAR function (PMID: 11035039, 15013427). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on EDAR protein function. ClinVar contains an entry for this variant (Variation ID: 5853). This missense change has been observed in individual(s) with autosomal dominant hypohidrotic ectodermal dysplasia (PMID: 10431241, 16435307, 18231121, 20979233, 23401279, 27657131). In at least one individual the variant was observed to be de novo. 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 glutamine, which is neutral and polar, at codon 420 of the EDAR protein (p.Arg420Gln). (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV005042867.1
First in ClinVar: May 12, 2024 Last updated: May 12, 2024 |
Comment:
The missense variant c.1259G>Ap.Arg420Gln in EDAR gene has been reported previously in heterozygous state in multiple individuals with Ectodermal Dysplasia Zeng B, et al., 2016, … (more)
The missense variant c.1259G>Ap.Arg420Gln in EDAR gene has been reported previously in heterozygous state in multiple individuals with Ectodermal Dysplasia Zeng B, et al., 2016, Cluzeau C, et al., 2011. Experimental studies have shown that this missense change affects EDAR function Shindo M, Chaudhary PM, 2004. The variant is novel not in any individuals in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. The amino acid Arginine at position 420 is changed to a Glutamine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by SIFT. The amino acid change p.Arg420Gln in EDAR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 20, 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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GeneDx
Accession: SCV000321592.7
First in ClinVar: Oct 09, 2016 Last updated: Oct 08, 2024 |
Comment:
Published functional studies demonstrate a damaging effect: R420Q disrupts NF-kB pathway activation and turns off repression of the Lef-1/b-catenin-dependent transcriptional activity leading to abnormal ectodermal … (more)
Published functional studies demonstrate a damaging effect: R420Q disrupts NF-kB pathway activation and turns off repression of the Lef-1/b-catenin-dependent transcriptional activity leading to abnormal ectodermal differentiation and hair follicle morphogenesis (PMID: 11035039, 15013427); Not observed in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17943131, 18231121, 15013427, 29364747, 20301291, 11035039, 31245878, 16435307, 10431241) (less)
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Pathogenic
(Oct 10, 2022)
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criteria provided, single submitter
Method: clinical testing
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Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant
Affected status: yes
Allele origin:
germline
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Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV003799096.2
First in ClinVar: Feb 13, 2023 Last updated: Mar 04, 2023 |
Comment:
PS3, PS4, PM1, PM2, PP3
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Pathogenic
(Aug 01, 1999)
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no assertion criteria provided
Method: literature only
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ECTODERMAL DYSPLASIA 10A, HYPOHIDROTIC/HAIR/TOOTH TYPE, AUTOSOMAL DOMINANT
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000026393.4
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
In all affected members of a family with autosomal dominant hypohidrotic ectodermal dysplasia (ECTD10A; 129490), Monreal et al. (1999) identified a G-to-A transition at nucleotide … (more)
In all affected members of a family with autosomal dominant hypohidrotic ectodermal dysplasia (ECTD10A; 129490), Monreal et al. (1999) identified a G-to-A transition at nucleotide 1259 in exon 12 of the EDAR gene that resulted in an arg-to-gln substitution at codon 420 (R420Q). (less)
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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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Eight Mutations of Three Genes (EDA, EDAR, and WNT10A) Identified in Seven Hypohidrotic Ectodermal Dysplasia Patients. | Zeng B | Genes | 2016 | PMID: 27657131 |
Mutations in WNT10A are frequently involved in oligodontia associated with minor signs of ectodermal dysplasia. | Plaisancié J | American journal of medical genetics. Part A | 2013 | PMID: 23401279 |
Only four genes (EDA1, EDAR, EDARADD, and WNT10A) account for 90% of hypohidrotic/anhidrotic ectodermal dysplasia cases. | Cluzeau C | Human mutation | 2011 | PMID: 20979233 |
Mutation screening of the Ectodysplasin-A receptor gene EDAR in hypohidrotic ectodermal dysplasia. | van der Hout AH | European journal of human genetics : EJHG | 2008 | PMID: 18231121 |
Mutations in EDAR account for one-quarter of non-ED1-related hypohidrotic ectodermal dysplasia. | Chassaing N | Human mutation | 2006 | PMID: 16435307 |
The ectodermal dysplasia receptor represses the Lef-1/beta-catenin-dependent transcription independent of NF-kappaB activation. | Shindo M | Biochemical and biophysical research communications | 2004 | PMID: 15013427 |
The ectodermal dysplasia receptor activates the nuclear factor-kappaB, JNK, and cell death pathways and binds to ectodysplasin A. | Kumar A | The Journal of biological chemistry | 2001 | PMID: 11035039 |
Mutations in the human homologue of mouse dl cause autosomal recessive and dominant hypohidrotic ectodermal dysplasia. | Monreal AW | Nature genetics | 1999 | PMID: 10431241 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=EDAR | - | - | - | - |
Text-mined citations for rs121908453 ...
HelpRecord last updated Oct 08, 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.