ClinVar Miner

Submissions for variant NM_022336.4(EDAR):c.1073G>A (p.Arg358Gln)

dbSNP: rs886039564
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx 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.
Invitae RCV001389818 SCV001591302 pathogenic Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant; Autosomal recessive hypohidrotic ectodermal dysplasia syndrome 2020-02-06 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect EDAR protein function (PMID: 21876339). This variant has been observed in individual(s) with autosomal recessive hypohidrotic ectodermal dysplasia (PMID: 21876339, 19438931). It has also been observed to segregate with autosomal dominant tooth agenesis in related individuals (PMID: 23991204). ClinVar contains an entry for this variant (Variation ID: 265471). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glutamine at codon 358 of the EDAR protein (p.Arg358Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine.
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.

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