ClinVar Miner

Submissions for variant NM_001399.5(EDA):c.866G>A (p.Arg289His) (rs876657641)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000223248 SCV000271219 likely pathogenic Partial congenital absence of teeth 2015-10-11 criteria provided, single submitter clinical testing 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.
Invitae RCV001054886 SCV001219244 pathogenic Hypohidrotic X-linked ectodermal dysplasia 2019-06-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 289 of the EDA protein (p.Arg289His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with ectodermal dysplasia in families (PMID: 26753551, Invitae). ClinVar contains an entry for this variant (Variation ID: 228257). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). 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, 27144394, 24487376). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Biotechnology Lab, Dept of Biomolecular Sciences, University of Urbino RCV001248822 SCV001366090 pathogenic Hypohidrotic X-linked ectodermal dysplasia; Tooth agenesis, selective, X-linked, 1 2020-06-01 criteria provided, single submitter clinical testing 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.