ClinVar Genomic variation as it relates to human health
NM_001399.5(EDA):c.1094T>C (p.Val365Ala)
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.1094T>C (p.Val365Ala)
Variation ID: 44185 Accession: VCV000044185.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq13.1 X: 70035527 (GRCh38) [ NCBI UCSC ] X: 69255377 (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 Feb 24, 2015 Feb 20, 2024 Dec 25, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001399.5:c.1094T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001390.1:p.Val365Ala missense NM_001005609.2:c.1088T>C NP_001005609.1:p.Val363Ala missense NM_001005612.3:c.1079T>C NP_001005612.2:p.Val360Ala missense NC_000023.11:g.70035527T>C NC_000023.10:g.69255377T>C NG_009809.2:g.424461T>C - Protein change
- V365A, V360A, V363A
- Other names
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- Canonical SPDI
- NC_000023.11:70035526:T:C
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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.
The Genome Aggregation Database (gnomAD), exomes 0.00001
The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00004
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 |
571 | 709 |
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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Likely pathogenic (1) |
criteria provided, single submitter
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Sep 20, 2011 | RCV000037161.6 | |
Pathogenic (2) |
criteria provided, single submitter
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Dec 25, 2023 | RCV000542700.11 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 22, 2017 | RCV000624502.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 24, 2022 | RCV001577971.6 | |
Likely pathogenic (1) |
criteria provided, single submitter
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- | RCV003335068.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Aug 12, 2023 | RCV003485530.1 |
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
(Sep 20, 2011)
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criteria provided, single submitter
Method: clinical testing
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Partial congenital absence of teeth
(X-linked inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000060818.5
First in ClinVar: May 03, 2013 Last updated: Feb 24, 2015 |
Comment:
The Val365Ala variant in EDA has been reported in one family with X-linked non-s yndromic tooth agenesis, showing segregation with clinical features in at least … (more)
The Val365Ala variant in EDA has been reported in one family with X-linked non-s yndromic tooth agenesis, showing segregation with clinical features in at least 6 meioses in this family. In addition, this variant was absent from over 140 co ntrol chromosomes (Mues 2010). Valine (Val) at position 365 is highly conserved across evolutionarily distant species suggesting that a change to the amino acid may not be tolerated. However, computational analyses (biochemical amino acid properties, homology, PolyPhen2, SIFT, AlignGVGD) do not provide strong support for or against pathogenicity. Furthermore, functional studies suggest that the Val365Arg variant may affect cell signaling pathways, but does not show the same decrease in receptor binding seen in classic HED variants (Mues 2010). In summ ary, this variant is likely to be pathogenic in association with tooth agenesis, but its role the hypohidrotic ectodermal dysplasia phenotype remains unclear. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Mar 22, 2017)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV000741907.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Delayed fine motor development (present) , Dental crowding (present) , Agenesis of permanent teeth (present) , Joint swelling (present) , Muscle cramps (present) , Pain … (more)
Delayed fine motor development (present) , Dental crowding (present) , Agenesis of permanent teeth (present) , Joint swelling (present) , Muscle cramps (present) , Pain (present) , Relative macrocephaly (present) , Premature birth (present) , Arthralgia (present) , Paresthesia (present) (less)
Sex: male
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Pathogenic
(Jun 24, 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: SCV001805476.3
First in ClinVar: Aug 21, 2021 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect with reduced receptor binding and signaling capability compared to wildtype (Mues et al., 2010); Missense variants in this … (more)
Published functional studies demonstrate a damaging effect with reduced receptor binding and signaling capability compared to wildtype (Mues et al., 2010); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19623212, 24391090, 20628232, 25203534, 21457804, 26325558, 19921643, 11295832, 23553579, 26345974, 24664614, 12949972, 22350046) (less)
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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EDA-related disorders
Affected status: yes
Allele origin:
germline
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Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV004046192.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
This variant has been observed to segregate with disease in a family with multiple individuals with selective tooth agenesis (PMID: 19623212). Functional studies suggest that … (more)
This variant has been observed to segregate with disease in a family with multiple individuals with selective tooth agenesis (PMID: 19623212). Functional studies suggest that the c.1094T>C (p.Val365Ala) variant may affect cell signaling pathways (PMID: 19623212). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.001095% (2/182595) and thus is presumed to be rare. The c.1094T>C (p.Val365Ala) variant affects a highly conserved amino acid. In silico tools used to predict the effect of this variant on protein function yield discordant results. Based on the available evidence, the c.1094T>C p.Val365Ala variant is classified as Likely Pathogenic. (less)
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Likely pathogenic
(Aug 12, 2023)
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criteria provided, single submitter
Method: clinical testing
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Tooth agenesis, selective, X-linked, 1
Affected status: unknown
Allele origin:
germline
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Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV004239086.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
Comment:
This EDA variant (rs397516654) is rare (<0.1%) in a large population dataset (gnomAD: 2/182595 total alleles; 0.001%; 1 hemizygote) and has been reported in ClinVar. … (more)
This EDA variant (rs397516654) is rare (<0.1%) in a large population dataset (gnomAD: 2/182595 total alleles; 0.001%; 1 hemizygote) and has been reported in ClinVar. This variant has been reported in a multi-generation family with X-linked nonsyndromic tooth agenesis. This amino acid substitution is located in the C-terminal quarter of the TNF-like receptor-binding domain, near the dimer interface where receptor binding is predicted to occur; in vitro experimental studies demonstrate that the signaling capacity of protein constructs containing p.Val365Ala are impaired even though cellular production, export and receptor binding are readily detectable. Bioinformatic analysis predicts that this missense variant would not affect normal exon 8 splicing, although this has not been confirmed experimentally to our knowledge. We consider c.1094T>C (p.Val365Ala) to be likely pathogenic for X-linked selected tooth agenesis-1. (less)
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Pathogenic
(Dec 25, 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: SCV000630019.10
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 365 of the EDA protein (p.Val365Ala). … (more)
This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 365 of the EDA protein (p.Val365Ala). This variant is present in population databases (rs397516654, gnomAD 0.003%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with selective tooth agenesis in a single, large family (PMID: 19623212). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 44185). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects EDA function (PMID: 19623212). For these reasons, this variant has been classified as Pathogenic. (less)
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not provided
(-)
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no classification provided
Method: phenotyping only
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Hypohidrotic X-linked ectodermal dysplasia
Affected status: unknown
Allele origin:
unknown
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GenomeConnect - Invitae Patient Insights Network
Accession: SCV004037542.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
Comment:
Variant classified as Pathogenic and reported on 10-31-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report … (more)
Variant classified as Pathogenic and reported on 10-31-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Clinical Features:
Myopia (present) , Abnormal oral cavity morphology (present) , Abnormal intestine morphology (present)
Indication for testing: Family Testing
Age: 60-69 years
Sex: female
Method: Single Gene Sequencing|
Testing laboratory: Invitae
Date variant was reported to submitter: 2017-10-31
Testing laboratory interpretation: Pathogenic
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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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Functional analysis of Ectodysplasin-A mutations causing selective tooth agenesis. | Mues G | European journal of human genetics : EJHG | 2010 | PMID: 19623212 |
Text-mined citations for rs397516654 ...
HelpRecord last updated Feb 28, 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.