Submissions for variant NM_022336.4(EDAR):c.607G>A (p.Val203Ile)

gnomAD frequency: 0.00024  dbSNP: rs148212997

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000380246	SCV000415849	uncertain significance	Hypohidrotic Ectodermal Dysplasia, Dominant	2016-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000523863	SCV000622015	uncertain significance	not provided	2017-10-25	criteria provided, single submitter	clinical testing	The V203I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant is observed in 9/24008 (0.038%) alleles from individuals of African background in large population cohorts (Lek et al., 2016). V203I is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Illumina Laboratory Services, Illumina	RCV001131110	SCV001290717	uncertain significance	Hypohidrotic ectodermal dysplasia	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Ambry Genetics	RCV002521262	SCV003724797	uncertain significance	Inborn genetic diseases	2021-10-20	criteria provided, single submitter	clinical testing	The c.607G>A (p.V203I) alteration is located in exon 7 (coding exon 6) of the EDAR gene. This alteration results from a G to A substitution at nucleotide position 607, causing the valine (V) at amino acid position 203 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Invitae	RCV003765912	SCV004581926	uncertain significance	Ectodermal dysplasia 10A, hypohidrotic/hair/nail type, autosomal dominant; Autosomal recessive hypohidrotic ectodermal dysplasia syndrome	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 203 of the EDAR protein (p.Val203Ile). This variant is present in population databases (rs148212997, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with EDAR-related conditions. ClinVar contains an entry for this variant (Variation ID: 330709). 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 EDAR protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.