Submissions for variant NM_022336.4(EDAR):c.1259G>A (p.Arg420Gln)

dbSNP: rs121908453

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000255701	SCV000225690	likely pathogenic	not provided	2016-04-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000255701	SCV000321592	pathogenic	not provided	2016-07-25	criteria provided, single submitter	clinical testing	The R420Q missense variant in the EDAR gene has been reported previously in a family with autosomal dominant hypohidrotic ectodermal dysplasia (Monreal et al.,1999). The R420Q variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position in the EDAR death domain (Sabeti et al., 2007) that is conserved across species. Functional studies show that the R420Q variant disrupts NF-kB pathway activation and turns off repression of the Lef-1/b-catenin- dependent transcriptional activity leading to abnormal ectodermal differentiation and hair follicle morphogenesis (Shindo et al., 2004).
SIB Swiss Institute of Bioinformatics	RCV000755721	SCV000883203	pathogenic	Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant	2018-10-15	criteria provided, single submitter	curation	This variant is interpreted as Pathogenic, for Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PM6 => Assumed de novo, but without confirmation of paternity and maternity (https://www.ncbi.nlm.nih.gov/pubmed/16435307). PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (https://www.ncbi.nlm.nih.gov/pubmed/18231121) (https://www.ncbi.nlm.nih.gov/pubmed/10431241). PM1 => Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation (http://www.uniprot.org/uniprot/Q9UNE0). PS3 => Well-established functional studies show a deleterious effect (https://www.ncbi.nlm.nih.gov/pubmed/11035039).
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000755721	SCV000923715	likely pathogenic	Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant	2019-01-01	criteria provided, single submitter	clinical testing
Invitae	RCV001050412	SCV001214517	pathogenic	Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant; Autosomal recessive hypohidrotic ectodermal dysplasia syndrome	2023-03-08	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects EDAR function (PMID: 11035039, 15013427). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on EDAR protein function. ClinVar contains an entry for this variant (Variation ID: 5853). This missense change has been observed in individual(s) with autosomal dominant hypohidrotic ectodermal dysplasia (PMID: 10431241, 16435307, 18231121, 20979233, 23401279, 27657131). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 420 of the EDAR protein (p.Arg420Gln).
Baylor Genetics	RCV001334149	SCV001526904	likely pathogenic	Ectodermal dysplasia 11B, hypohidrotic/hair/tooth type, autosomal recessive	2018-01-25	criteria provided, single submitter	clinical testing	This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been reported in a family with autosomal dominant hypohidrotic ectodermal dysplasia [PMID: 10431241] and was shown to decrease the EDAR protein's ability to repress the Lef-1/b-catenin activity in vitro [PMID: 15013427]
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000755721	SCV003799096	pathogenic	Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant	2022-10-10	criteria provided, single submitter	clinical testing	PS3, PS4, PM1, PM2, PP3
OMIM	RCV000006211	SCV000026393	pathogenic	Ectodermal dysplasia 10a, hypohidrotic/hair/tooth type, autosomal dominant	1999-08-01	no assertion criteria provided	literature only