Submissions for variant NM_001399.5(EDA):c.871G>A (p.Gly291Arg)

dbSNP: rs397516677

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037189	SCV000060846	pathogenic	Hypohidrotic X-linked ectodermal dysplasia	2011-09-17	criteria provided, single submitter	clinical testing	The Gly291Arg variant in EDA has been reported in at least 11 individuals with X -linked hypohidrotic ectodermal dysplasia. It was reported as de novo in two of these individuals and was absent from over 300 control chromosomes (Bayes 1998, Cluzeau 2011, Schneider 2001, Schneider 2011, Sekiguchi 2005, LMM unpublished d ata). In summary, this variant meets our criteria to be classified as pathogeni c.
GeneDx	RCV000256153	SCV000321584	pathogenic	not provided	2021-04-05	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); Identified in multiple patients with X-linked hypohidrotic ectodermal dysplasia referred for genetic testing at GeneDx and in published literature (Schneider et al., 2001; Bayes et al., 1998; Cluzeau et al., 2011); This variant is associated with the following publications: (PMID: 9736768, 22032522, 23553579, 18231121, 21357618, 24033266, 20979233, 19278982, 11279189, 31129666)
Invitae	RCV000037189	SCV001220181	pathogenic	Hypohidrotic X-linked ectodermal dysplasia	2022-07-24	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 291 of the EDA protein (p.Gly291Arg). This missense change has been observed in individual(s) with hypohidrotic/anhidrotic ectodermal dysplasia (PMID: 9736768, 20979233, 21357618, 22032522, 23553579). This variant is also known as c.1113G>A. ClinVar contains an entry for this variant (Variation ID: 44211). 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.
Medical Molecular Genetics Department, National Research Center	RCV000037189	SCV001480044	pathogenic	Hypohidrotic X-linked ectodermal dysplasia	2021-02-13	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003398602	SCV004121797	pathogenic	Anhidrotic ectodermal dysplasia	2023-10-18	criteria provided, single submitter	clinical testing	Variant summary: EDA c.871G>A (p.Gly291Arg) results in a non-conservative amino acid change located in a critical position within the Tumour necrosis factor domain (IPR006052) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183325 control chromosomes. c.871G>A has been reported in the literature in multiple individuals affected with Hypohidrotic Ectodermal Dysplasia (example, Bayes_1998, Sekiguchi_2005, Zeng_2015, Kang_2022, Park_2019). These data indicate that the variant is very 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: 15663448, 9736768, 26411740, 36071541, 31129666, 11279189, 18231121). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.