Submissions for variant NM_001399.5(EDA):c.206G>T (p.Arg69Leu)

gnomAD frequency: 0.00312  dbSNP: rs132630309

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000218834	SCV000269062	benign	not specified	2015-04-03	criteria provided, single submitter	clinical testing	p.Arg69Leu in exon 1 of EDA: This variant has been reported in 5 probands with X LHED, one of whom also carried a pathogenic variant in the same gene (Kere1996, Vincent 2001, Schneider 2011, Dietz 2013). However, this variant is not expected to have clinical significance because it has been identified in 0.5% (231/47072 ) of European chromosomes (94 hemizygotes) by the Exome Aggregation Consortium ( ExAC, http://exac.broadinstitute.org; dbSNP rs132630309).
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000432524	SCV000511232	benign	not provided	2017-01-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000432524	SCV000512921	likely benign	not provided	2019-02-15	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 8696334, 24631698, 26600092)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000432524	SCV000603413	benign	not provided	2023-11-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000011779	SCV000630022	benign	Hypohidrotic X-linked ectodermal dysplasia	2024-01-29	criteria provided, single submitter	clinical testing
Mendelics	RCV000011779	SCV001141902	uncertain significance	Hypohidrotic X-linked ectodermal dysplasia	2019-05-28	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000011779	SCV001652764	uncertain significance	Hypohidrotic X-linked ectodermal dysplasia	2021-05-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000218834	SCV003844898	benign	not specified	2023-02-17	criteria provided, single submitter	clinical testing	Variant summary: EDA c.206G>T (p.Arg69Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0029 in 181348 control chromosomes in the gnomAD database, including 201 hemizygotes and 1 homozygote. The high occurrence of hemizygotes suggests that the variant is benign. Although the variant, c.206G>T, has been reported in the literature in individuals affected with Hypohidrotic Ectodermal Dysplasia or related phenotypes (e.g. Kere_1996, Vincent_2001, Stagi_2009, Schneider_2011, Dietz_2013, Bonds_2014, Burger_2014, Ferstl_2018), however, no evidence for cosegregation was reported. In addition, in some of these cases co-occurrences with other pathogenic variants have been reported, which could explain the phenotype (EDA c.991C>T (p.Gln331Ter), Dietz_2013; EDA c.467G>A (p.Arg156His), Stagi_2009; TP63 c.952C>T (p.Arg318Cys), Ferstl_2018), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments, including pathogenic (n=1), uncertain significance (n=2), and benign (n=4) / likely benign (n=2). Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV000432524	SCV004165281	likely benign	not provided	2023-10-01	criteria provided, single submitter	clinical testing	EDA: PP3, BS2
OMIM	RCV000011779	SCV000032011	pathogenic	Hypohidrotic X-linked ectodermal dysplasia	1996-08-01	flagged submission	literature only
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000011779	SCV000746316	pathogenic	Hypohidrotic X-linked ectodermal dysplasia	2017-12-03	flagged submission	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000432524	SCV001743347	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000432524	SCV001797841	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000432524	SCV001927347	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000218834	SCV001971936	benign	not specified		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000011779	SCV002087192	likely benign	Hypohidrotic X-linked ectodermal dysplasia	2020-01-17	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003894799	SCV004725874	likely benign	EDA-related disorder	2022-06-14	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).