Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clinical Genomics Laboratory, |
RCV006645802 | SCV007538203 | likely pathogenic | EDAR-related disorder | 2022-02-23 | criteria provided, single submitter | clinical testing | The p.Arg358Gln variant in the EDAR gene has been previously reported in the homozygous state in at least 3 individuals with hypohidrotic ectodermal dysplasia (PMID: 19438931; PMID: 21876339; PMID: 20979233). This variant has also been previously reported in the heterozygous state in 1 individual with hypohidrotic ectodermal dysplasia (PMID: 31796081), and in 3 individuals from 1 family with nonsyndromic tooth agenesis (PMID: 23991204). This variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is located in an established functional domain of the EDAR protein known as the death domain (PMID: 11780064). Other pathogenic/likely pathogenic variants have been described in this domain (PMID: 20979233). A functional study of the p.Arg358Gln variant demonstrated this variant abolishes protein-protein interaction with EDARADD and markedly reduces activation of the downstream NF-kB signaling (PMID: 21876339). Computational tools predict that the p.Arg358Gln variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Arg358Gln variant as likely pathogenic for autosomal dominant and autosomal recessive EDAR-related disease based on the information above. [ACMG evidence codes used: PM1; PM2; PM3; PP1; PP3; PS3_Supporting] |
| 3billion | RCV001808722 | SCV002059129 | pathogenic | Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant | 2022-01-03 | criteria provided, single submitter | clinical testing | The variant has been observed in multiple (>3) similarly affected unrelated individuals (ClinVar ID: VCV000265471, PMID:19438931, PMID: 23991204, PMID: 21876339, PS4_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 21876339, PS3_S). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.74, PP3_P). A missense variant is a common mechanism associated with Ectodermal dysplasia 10A (PP2_P).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. |
| Labcorp Genetics |
RCV001389818 | SCV001591302 | pathogenic | Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant; Autosomal recessive hypohidrotic ectodermal dysplasia syndrome | 2025-07-06 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 358 of the EDAR protein (p.Arg358Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive hypohidrotic ectodermal dysplasia (PMID: 19438931, 21876339, 23991204). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 265471). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt EDAR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects EDAR function (PMID: 21876339). For these reasons, this variant has been classified as Pathogenic. |
| Gene |
RCV000254918 | SCV000322412 | pathogenic | not provided | 2016-08-16 | criteria provided, single submitter | clinical testing | The R358Q pathogenic variant in the EDAR gene has been reported previously in association with hypohidrotic ectodermal dysplasia (HED) when present in the homozygous state (Shimomura et al., 2009; Masui et al., 2011), and has also been reported in the heterozygous state in three related individuals with tooth agenesis (Arte et al., 2013). The R358Q 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. The R358Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. Functional studies using transfected HEK293T cells showed that the R358Q EDAR protein lost affinity to EDARADD and markedly reduced activation of the downstream NF-kB signaling (Masui et al., 2011). We interpret R358Q as a pathogenic variant. |