ClinVar Genomic variation as it relates to human health

PS3, PS4, PM1, PM2, PM6

The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 27305980, 22428923, 25333067) and it has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 26273176, 18231121, 18821982, 20486090). In addition, It has been previously reported as de novo in a similarly affected individual (PMID: 27054699). In silico tool predictions suggest damaging effect of the variant on gene or gene product (3CNET: 0.764>=0.75). It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with X-linked hypohidrotic ectodermal dysplasia 1 (MIM#305100) and selective tooth agenesis (MIM#313500). (I) 0110 - This gene is associated with X-linked disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes, 0 hemizygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (21 heterozygotes, 0 homozygotes, 13 hemizygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the consensus furin motif (PMID: 11416205). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is well-reported in the literature and has been reported in at least ten individuals with hypohidrotic ectodermal dysplasia (HED) (ClinVar; PMID: 27054699; 27305980; 26273176). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. The variant resides within a consensus furin motif and in vitro studies demonstrated that this variant impacts protein cleavage (PMID: 11416205) (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

PS3, PM1, PM2, PP3, PP5

Published functional studies demonstrate a damaging effect (PMID: 11416205); Missense variants in this gene are often considered pathogenic (HGMD); Not observed in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22428923, 24033266, 11279189, 34573371, 23926003, 20486090, 18821982, 9683615, 27054699, 11378824, 28045201, 30417976, 31129666, 31924237, 34863015, 11416205)

The p.Arg155Cys variant in EDA has been reported in 6 affected males with X-link ed hypohidrotic ectodermal dysplasia (XLHED) and segregated with disease in 1 af fected male and 5 carrier females from 3 families (Monreal 1998, Schneider 2001, Fan 2008, Khabour 2010, Callea 2013, Zhu 2013). It was absent from large popula tion studies. Furthermore, this variant has been identified by our laboratory in 5 individuals with XLHED. This variant resides in the furin domain of EDA and i n-vitro functional studies suggest that this variant impacts protein cleavage (C hen, 2001). In summary, this variant meets our criteria to be classified as path ogenic for XLHED based upon segregation studies, absence from controls, and func tional evidence.

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 155 of the EDA protein (p.Arg155Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with X-linked hypohidrotic ectodermal dsyplasia (XLHED) (PMID: 9683615, 18231121, 18821982, 20486090, 22428923, 25333067, 26273176, 27054699, 27305980, 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. ClinVar contains an entry for this variant (Variation ID: 11035). 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. For these reasons, this variant has been classified as Pathogenic.