ClinVar Genomic variation as it relates to human health

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

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.

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individuals with X- linked hypohidrotic ectodermal dysplasia (Schneider 2001, He 2013, Clauss 2010, Schneider 2011, LMM unpublished data) and was absent from large population studi es.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).

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.

PS3, PM1, PM2, PP3, PP5

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.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with X-linked recessive ectodermal dysplasia 1, hypohidrotic (HED; MIM#305100) and X-linked dominant tooth agenesis, selective 1 (TA; MIM#313500). (I) 0108 - This gene is associated with both X-linked recessive and dominant disease. Female carriers of variants causing either condition may be normal or mildly affected, depending on skewed X-inactivation (PMID: 18510547, 16583127). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (260 heterozygotes, 2 homozygotes, 252 hemizygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar, and has been observed in individuals with hypohidrotic ectodermal dysplasia in the literature (PMID: 32176048). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign