ClinVar Miner

Submissions for variant NM_001399.5(EDA):c.546_581del (p.Asn185_Pro196del) (rs397516665)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000694688 SCV000060832 pathogenic Hypohidrotic X-linked ectodermal dysplasia 2018-01-30 criteria provided, single submitter clinical testing The p.Asn185_Pro196del (c.546_581del and c.553_588del) in-frame deletion in EDA has been identified in >10 individuals with X-linked hypohidrotic ectodermal dys plasia (de novo in at least 2 of these individuals) and segregated with disease in 1 affected relative (Bayes 1998, Monreal 1998, Schneider 2001, Lexner 2008, v an der Hout 2008, Schneider 2011, LMM data). Two different deletions (c.546_581d el and c.553_588del), which result in the same p.Asn185_Pro196del in-frame delet ion, have been reported in the individuals described above. In summary, this var iant meets criteria to be classified as pathogenic for X-linked hypohidrotic ect odermal dysplasia based upon its identification in affected individuals and de n ovo occurrences. ACMG/AMP Criteria applied: PS4; PM6_Strong; PM4; PP4.
Invitae RCV000694688 SCV000823145 pathogenic Hypohidrotic X-linked ectodermal dysplasia 2018-03-28 criteria provided, single submitter clinical testing This variant, c.546_581del, results in the deletion of 12 amino acids of the EDA protein (p.Asn185_Pro196del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in several individuals affected with hypohidrotic ectodermal dysplasia (PMID: 27305980, 18231121, 11279189, 9736768). This variant is also known as 789/795del in the literature. Additionally, a different deletion, c.553_588del (also reported as del794_829del) which results in the same protein effect has also been reported in several affected individuals, including at least one individual where the variant was reported de novo (PMID: 18231121, 21357618, 11279189, 9683615, 18510547, 9736768). ClinVar contains an entry for this variant (Variation ID: 44197). In vitro studies have shown that EDA protein with this in-frame deletion was able to form multimers via its collagen domain similar to wild type protein and was also able to functionally bind EDAR.  The authors state that the pathogenicity of this variant is likely not captured by the model used or the effect of the deletion is different in vivo.  Additional studies are needed in order to fully determine the mechanism by which this deletion causes disease (PMID: 11279189). For these reasons, this variant has been classified as Pathogenic.

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