Submissions for variant NM_001399.5(EDA):c.659_676del (p.217_219PGP[1])

dbSNP: rs876657686

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000402007	SCV000271359	pathogenic	Hypohidrotic X-linked ectodermal dysplasia	2015-07-22	criteria provided, single submitter	clinical testing	The p.Pro220_Pro225del variant in EDA has been reported in 4 individuals (3 mal es, 1 female) with clinical features of XLHED (Bayes 1998, Schneider 2011, Zhang 2011). This variant results in an in-frame deletion of 18 amino acids from the conserved Gly-X-Y repeat region of the collagen subdomain of the EDA protein. Se veral adjacent in-frame and frameshift deletions have also been identified in pa tients with clinical features of XLHED (Bayes 1998, Cluzeau 2011, Zhang 2011, LM M unpublished data), indicating that this region is intolerant to these types of variation. In summary, this variant meets our criteria to be classified as path ogenic for hypohidrotic ectodermal dysplasia in an X-linked manner.
Eurofins Ntd Llc (ga)	RCV000725905	SCV000340413	pathogenic	not provided	2016-03-30	criteria provided, single submitter	clinical testing
Invitae	RCV000402007	SCV000754738	pathogenic	Hypohidrotic X-linked ectodermal dysplasia	2023-10-03	criteria provided, single submitter	clinical testing	This variant, c.659_676del, results in the deletion of 6 amino acid(s) of the EDA protein (p.Pro220_Pro225del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with ectodermal dysplasia (PMID: 9736768, 21357618, 27305980). ClinVar contains an entry for this variant (Variation ID: 228338). This variant disrupts a region of the EDA protein in which other variant(s) (p.Pro220Leu) have been determined to be pathogenic (PMID: 25846883). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Medical Molecular Genetics Department, National Research Center	RCV000402007	SCV001762296	pathogenic	Hypohidrotic X-linked ectodermal dysplasia	2021-02-14	criteria provided, single submitter	research
GeneDx	RCV000725905	SCV001821181	pathogenic	not provided	2022-08-04	criteria provided, single submitter	clinical testing	In-frame deletion of 6 amino acids in a non-repeat region predicted to critically alter the protein; Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27305980, 25140498, 9736768, 20979233, 30394555, 24279917, 34573371, 21357618, 23553579, 24715423, 21457804, 26345974, 31924237)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235137	SCV003934789	pathogenic	Anhidrotic ectodermal dysplasia	2023-05-22	criteria provided, single submitter	clinical testing	Variant summary: EDA c.659_676del18 (p.Pro220_Pro225del) results in an in-frame deletion that is predicted to remove 6 amino acids from the encoded protein. The variant was absent in 146336 control chromosomes (gnomAD). c.659_676del18 has been reported in the literature in in both male and female individuals affected with Hypohidrotic Ectodermal Dysplasia, including a de novo occurrence (e.g. Bayes_1998, Schneider_2011, Cluzeau_2011, Ahmed_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 9736768, 21357618, 20979233, 34573371). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.