Submissions for variant NM_001399.5(EDA):c.457C>T (p.Arg153Cys)

dbSNP: rs397516662

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000592238	SCV000060826	pathogenic	Hypohidrotic X-linked ectodermal dysplasia	2014-04-12	criteria provided, single submitter	clinical testing	The Arg153Cys variant in EDA has been reported in at least 7 individuals with X- linked hypohidrotic ectodermal dysplasia (Schneider 2001, He 2013, Clauss 2010, Schneider 2011, LMM unpublished data) and was absent from large population studi es. Functional studies have shown that the Arg153Cys variant impacts normal prot ein function (Chen 2001). This variant is located within a critical cleavage reg ion and several other pathogenic variants in the EDA gene are also found within this region. In summary, this variant meets our criteria to be classified as pat hogenic (http://pcpgm.partners.org/LMM).
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000420111	SCV000510987	pathogenic	not provided	2016-06-08	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000420111	SCV000709338	pathogenic	not provided	2017-06-15	criteria provided, single submitter	clinical testing
Invitae	RCV000592238	SCV000833225	pathogenic	Hypohidrotic X-linked ectodermal dysplasia	2023-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 153 of the EDA protein (p.Arg153Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ectodermal dysplasia (PMID: 11279189, 20236127, 21357618, 21457804, 22875504, 24312213). ClinVar contains an entry for this variant (Variation ID: 44193). 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 EDA protein function. Experimental studies have shown that this missense change affects EDA function (PMID: 11279189, 11416205). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000592238	SCV001524090	pathogenic	Hypohidrotic X-linked ectodermal dysplasia	2019-12-18	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
3billion	RCV000592238	SCV002573127	pathogenic	Hypohidrotic X-linked ectodermal dysplasia	2022-09-01	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 11279189 , 11416205). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.57; 3Cnet: 0.87). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 11279189 , 20236127 , 21357618 , 21457804 , 22875504 , 24312213). A different missense change at the same codon (p.Arg153His) has been reported to be associated with EDA-related disorder (PMID: 24724966). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000592238	SCV002577528	pathogenic	Hypohidrotic X-linked ectodermal dysplasia	2021-11-05	criteria provided, single submitter	clinical testing	PS3, PM1, PM2, PP3, PP5
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003478983	SCV004222819	pathogenic	Anhidrotic ectodermal dysplasia	2023-11-17	criteria provided, single submitter	clinical testing	Variant summary: EDA c.457C>T (p.Arg153Cys) 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 was absent in 182427 control chromosomes (gnomAD). c.457C>T has been reported in the literature in multiple individuals affected with Hypohidrotic Ectodermal Dysplasia (e.g. Schneider_2001, Burger_2014, Wolfhart_2016, Martinez-Romero_2019), and at least one case was reported as having a de novo origin. These data indicate that the variant is very likely to be associated with disease. At least two publications reports experimental evidence evaluating an impact on protein function (Schneider_2001, Chen_2001), finding that the variant interferes with proteolytic processing. The following publications have been ascertained in the context of this evaluation (PMID: 11279189, 11416205, 24715423, 27305980, 31796081). Seven 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.
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000592238	SCV000746049	pathogenic	Hypohidrotic X-linked ectodermal dysplasia	2017-09-18	no assertion criteria provided	clinical testing