Submissions for variant NM_001399.5(EDA):c.1069C>T (p.Arg357Trp)

dbSNP: rs886039347

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255432	SCV000321586	pathogenic	not provided	2022-08-23	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23991204, 28045201)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000532383	SCV000630018	pathogenic	Hypohidrotic X-linked ectodermal dysplasia	2023-12-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 357 of the EDA protein (p.Arg357Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of X-linked hypohidrotic ectodermal dysplasia (PMID: 28045201, 31796081; Invitae). ClinVar contains an entry for this variant (Variation ID: 265112). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV000255432	SCV002501008	likely pathogenic	not provided	2021-04-22	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University Hospital Muenster	RCV004584376	SCV002577761	likely pathogenic	See cases	2019-07-17	criteria provided, single submitter	clinical testing	ACMG categories: PM1,PM2,PP1,PP3
CeGaT Center for Human Genetics Tuebingen	RCV000255432	SCV004702614	likely pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	EDA: PM1, PM2, PM5, PS4:Moderate
PreventionGenetics, part of Exact Sciences	RCV004730918	SCV005335765	likely pathogenic	EDA-related disorder	2024-05-30	no assertion criteria provided	clinical testing	The EDA c.1069C>T variant is predicted to result in the amino acid substitution p.Arg357Trp. This variant has been reported in the hemizygous state in individuals with hypohidrotic ectodermal dysplasia (Arte et al. 2013. PubMed ID: 23991204; Monroy-Jaramillo et al. 2017. PubMed ID: 28045201; Martínez-Romero et al 2019. PubMed ID: 31796081). This variant has not been reported in a large population database, indicating this variant is rare and has been interpreted as pathogenic and likely pathogenic by other laboratories in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/265112/). Additionally, a different missense change impacting the same amino acid (c.1070G>C, p.Arg357Pro) has been reported in individuals with hypohidrotic ectodermal dysplasia (Monreal et al. 1998. PubMed ID: 9683615; Goodwin et al. 2014. PubMed ID: 25333067), indicating the p.Arg357 residue may be important for EDA function. Taken together, the c.1069C>T (p.Arg357Trp) variant is interpreted as likely pathogenic.