p.Arg69Leu in exon 1 of EDA: This variant has been reported in 5 probands with X LHED, one of whom also carried a pathogenic variant in the same gene (Kere1996, Vincent 2001, Schneider 2011, Dietz 2013). However, this variant is not expected to have clinical significance because it has been identified in 0.5% (231/47072 ) of European chromosomes (94 hemizygotes) by the Exome Aggregation Consortium ( ExAC, http://exac.broadinstitute.org; dbSNP rs132630309).
ClinVar Genomic variation as it relates to human health
NM_001399.5(EDA):c.206G>T (p.Arg69Leu)
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.
(17)
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.
Conflicting classifications of pathogenicity
Uncertain significance(2); Benign(5); Likely benign(2)
Uncertain significance(2); Benign(5); Likely benign(2)
17
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001399.5(EDA):c.206G>T (p.Arg69Leu)
Variation ID: 11032 Accession: VCV000011032.55
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: Xq13.1 X: 69616514 (GRCh38) [ NCBI UCSC ] X: 68836358 (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 Aug 22, 2016 Dec 22, 2024 Sep 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001399.5:c.206G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001390.1:p.Arg69Leu missense NM_001005609.2:c.206G>T NP_001005609.1:p.Arg69Leu missense NM_001005610.4:c.206G>T NP_001005610.2:p.Arg69Leu missense NM_001005612.3:c.206G>T NP_001005612.2:p.Arg69Leu missense NM_001005613.4:c.206G>T NP_001005613.1:p.Arg69Leu missense NC_000023.11:g.69616514G>T NC_000023.10:g.68836358G>T NG_009809.2:g.5448G>T Q92838:p.Arg69Leu - Protein change
- R69L
- Other names
- -
- Canonical SPDI
- NC_000023.11:69616513:G:T
-
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.
-
0.00132 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
1000 Genomes Project 0.00132
1000 Genomes Project 30x 0.00166
The Genome Aggregation Database (gnomAD), exomes 0.00286
Trans-Omics for Precision Medicine (TOPMed) 0.00296
The Genome Aggregation Database (gnomAD) 0.00312
Exome Aggregation Consortium (ExAC) 0.00314
- 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. |
|||
| EDA | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
592 | 734 | |
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. |
|---|---|---|---|---|
| Conflicting classifications of pathogenicity (6) |
criteria provided, conflicting classifications
|
Jan 29, 2024 | RCV000011779.33 | |
| Benign (3) |
criteria provided, multiple submitters, no conflicts
|
Feb 17, 2023 | RCV000218834.19 | |
| Benign/Likely benign (7) |
criteria provided, multiple submitters, no conflicts
|
Sep 1, 2024 | RCV000432524.33 | |
|
EDA-related disorder
|
Likely benign (1) |
no assertion criteria provided
|
Jun 14, 2022 | RCV003894799.2 |
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
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. |
|
|---|---|---|---|---|---|
|
Benign
(Jan 05, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000511232.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Benign
(Apr 03, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000269062.2
First in ClinVar: May 29, 2016 Last updated: Mar 08, 2017 |
Comment:
p.Arg69Leu in exon 1 of EDA: This variant has been reported in 5 probands with X LHED, one of whom also carried a pathogenic variant … (more)
p.Arg69Leu in exon 1 of EDA: This variant has been reported in 5 probands with X LHED, one of whom also carried a pathogenic variant in the same gene (Kere1996, Vincent 2001, Schneider 2011, Dietz 2013). However, this variant is not expected to have clinical significance because it has been identified in 0.5% (231/47072 ) of European chromosomes (94 hemizygotes) by the Exome Aggregation Consortium ( ExAC, http://exac.broadinstitute.org; dbSNP rs132630309). (less)
Number of individuals with the variant: 1
|
|
|
Uncertain significance
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Hypohidrotic X-linked ectodermal dysplasia
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001141902.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
|
Benign
(Feb 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003844898.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
Variant summary: EDA c.206G>T (p.Arg69Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging … (more)
Variant summary: EDA c.206G>T (p.Arg69Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0029 in 181348 control chromosomes in the gnomAD database, including 201 hemizygotes and 1 homozygote. The high occurrence of hemizygotes suggests that the variant is benign. Although the variant, c.206G>T, has been reported in the literature in individuals affected with Hypohidrotic Ectodermal Dysplasia or related phenotypes (e.g. Kere_1996, Vincent_2001, Stagi_2009, Schneider_2011, Dietz_2013, Bonds_2014, Burger_2014, Ferstl_2018), however, no evidence for cosegregation was reported. In addition, in some of these cases co-occurrences with other pathogenic variants have been reported, which could explain the phenotype (EDA c.991C>T (p.Gln331Ter), Dietz_2013; EDA c.467G>A (p.Arg156His), Stagi_2009; TP63 c.952C>T (p.Arg318Cys), Ferstl_2018), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments, including pathogenic (n=1), uncertain significance (n=2), and benign (n=4) / likely benign (n=2). Based on the evidence outlined above, the variant was classified as benign. (less)
|
|
|
Benign
(Nov 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000603413.4
First in ClinVar: Mar 08, 2017 Last updated: Feb 20, 2024 |
|
|
|
Benign
(Jan 29, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hypohidrotic X-linked ectodermal dysplasia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000630022.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
|
|
|
Uncertain significance
(May 18, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hypohidrotic X-linked ectodermal dysplasia
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV001652764.1
First in ClinVar: May 28, 2021 Last updated: May 28, 2021 |
Sex: mixed
|
|
|
Likely benign
(Feb 15, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000512921.4
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
This variant is associated with the following publications: (PMID: 8696334, 24631698, 26600092)
|
|
|
Likely benign
(Sep 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004165281.11
First in ClinVar: Nov 20, 2023 Last updated: Dec 22, 2024 |
Comment:
EDA: PP3, BS2
Number of individuals with the variant: 5
|
|
|
Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001927347.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
|
|
|
Likely benign
(Jun 14, 2022)
|
no assertion criteria provided
Method: clinical testing
|
EDA-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004725874.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
|
|
|
Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001797841.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
|
|
|
Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001743347.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
|
|
|
Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001971936.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
|
|
|
Likely benign
(Jan 17, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Christ-Siemens-Touraine syndrome
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002087192.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
|
|
Pathogenic
(Dec 03, 2017)
|
Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
|
Hypohidrotic X-linked ectodermal dysplasia
Affected status: yes
Allele origin:
inherited
|
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000746316.1
First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
Age: 0-9 years
Sex: male
Geographic origin: Iran
|
|
|
Pathogenic
(Aug 01, 1996)
|
Flagged submission
flagged submission
Method: literature only
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
|
ECTODERMAL DYSPLASIA 1, HYPOHIDROTIC/HAIR/TOOTH TYPE, X-LINKED
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000032011.3
First in ClinVar: Apr 04, 2013 Last updated: Aug 23, 2022 |
Comment on evidence:
In a family with X-linked hypohidrotic ectodermal dysplasia (XHED, ECTD1; 305100) from the United Kingdom and another from the U.S., Kere et al. (1996) found … (more)
In a family with X-linked hypohidrotic ectodermal dysplasia (XHED, ECTD1; 305100) from the United Kingdom and another from the U.S., Kere et al. (1996) found an association between EDA and a point mutation, a G-to-T transversion at nucleotide 448 resulting in an arg69-to-leu amino acid substitution. (less)
|
|
| click to load more click to collapse | |||||
| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
Variant summary: EDA c.206G>T (p.Arg69Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0029 in 181348 control chromosomes in the gnomAD database, including 201 hemizygotes and 1 homozygote. The high occurrence of hemizygotes suggests that the variant is benign. Although the variant, c.206G>T, has been reported in the literature in individuals affected with Hypohidrotic Ectodermal Dysplasia or related phenotypes (e.g. Kere_1996, Vincent_2001, Stagi_2009, Schneider_2011, Dietz_2013, Bonds_2014, Burger_2014, Ferstl_2018), however, no evidence for cosegregation was reported. In addition, in some of these cases co-occurrences with other pathogenic variants have been reported, which could explain the phenotype (EDA c.991C>T (p.Gln331Ter), Dietz_2013; EDA c.467G>A (p.Arg156His), Stagi_2009; TP63 c.952C>T (p.Arg318Cys), Ferstl_2018), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments, including pathogenic (n=1), uncertain significance (n=2), and benign (n=4) / likely benign (n=2). Based on the evidence outlined above, the variant was classified as benign.
Comment:
This variant is associated with the following publications: (PMID: 8696334, 24631698, 26600092)
Comment:
EDA: PP3, BS2
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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:
p.Arg69Leu in exon 1 of EDA: This variant has been reported in 5 probands with X LHED, one of whom also carried a pathogenic variant in the same gene (Kere1996, Vincent 2001, Schneider 2011, Dietz 2013). However, this variant is not expected to have clinical significance because it has been identified in 0.5% (231/47072 ) of European chromosomes (94 hemizygotes) by the Exome Aggregation Consortium ( ExAC, http://exac.broadinstitute.org; dbSNP rs132630309).
Comment:
Variant summary: EDA c.206G>T (p.Arg69Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0029 in 181348 control chromosomes in the gnomAD database, including 201 hemizygotes and 1 homozygote. The high occurrence of hemizygotes suggests that the variant is benign. Although the variant, c.206G>T, has been reported in the literature in individuals affected with Hypohidrotic Ectodermal Dysplasia or related phenotypes (e.g. Kere_1996, Vincent_2001, Stagi_2009, Schneider_2011, Dietz_2013, Bonds_2014, Burger_2014, Ferstl_2018), however, no evidence for cosegregation was reported. In addition, in some of these cases co-occurrences with other pathogenic variants have been reported, which could explain the phenotype (EDA c.991C>T (p.Gln331Ter), Dietz_2013; EDA c.467G>A (p.Arg156His), Stagi_2009; TP63 c.952C>T (p.Arg318Cys), Ferstl_2018), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments, including pathogenic (n=1), uncertain significance (n=2), and benign (n=4) / likely benign (n=2). Based on the evidence outlined above, the variant was classified as benign.
Comment:
This variant is associated with the following publications: (PMID: 8696334, 24631698, 26600092)
Comment:
EDA: PP3, BS2
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Sweating ability of patients with p63-associated syndromes. | Ferstl P | European journal of pediatrics | 2018 | PMID: 30088137 |
| Genotype-phenotype correlation in boys with X-linked hypohidrotic ectodermal dysplasia. | Burger K | American journal of medical genetics. Part A | 2014 | PMID: 24715423 |
| Is there a link between ovarian cancer and tooth agenesis? | Bonds J | European journal of medical genetics | 2014 | PMID: 24631698 |
| Early respiratory and ocular involvement in X-linked hypohidrotic ectodermal dysplasia. | Dietz J | European journal of pediatrics | 2013 | PMID: 23553579 |
| Sweating ability and genotype in individuals with X-linked hypohidrotic ectodermal dysplasia. | Schneider H | Journal of medical genetics | 2011 | PMID: 21357618 |
| Growth hormone neurosecretory dysfunction in a boy with hypohidrotic/anhidrotic ectodermal dysplasia: definition of short stature, molecular characterization and long-term hGH replacement treatment to final height. | Stagi S | Journal of pediatric endocrinology & metabolism : JPEM | 2009 | PMID: 19960895 |
| Mutational spectrum of the ED1 gene in X-linked hypohidrotic ectodermal dysplasia. | Vincent MC | European journal of human genetics : EJHG | 2001 | PMID: 11378824 |
| X-linked anhidrotic (hypohidrotic) ectodermal dysplasia is caused by mutation in a novel transmembrane protein. | Kere J | Nature genetics | 1996 | PMID: 8696334 |
Text-mined citations for rs132630309 ...
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 Jan 19, 2025
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.