ClinVar Miner

Submissions for variant NM_001399.5(EDA):c.494G>C (p.Gly165Ala) (rs1057521131)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000432953 SCV000521159 likely pathogenic not provided 2018-03-12 criteria provided, single submitter clinical testing The G165A variant in the EDA1 gene has been previously reported in kindreds displaying selective tooth agenesis (Mues et al., 2009). The variant has also been identified in individuals with features of HED at GeneDx. The variant is not observed in large population cohorts (Lek et al., 2016). The G165A variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Missense variants in nearby residues have been seen at GeneDx (S160N/R; E164A) and have been reported in the Human Gene Mutation Database (E164A) in association with HED (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic
Invitae RCV000822954 SCV000963783 uncertain significance Hypohidrotic X-linked ectodermal dysplasia 2018-10-03 criteria provided, single submitter clinical testing This sequence change replaces glycine with alanine at codon 165 of the EDA protein (p.Gly165Ala). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with clinical features of ectodermal dysplasia (PMID: 19504606, Invitae) and segregated with tooth agenesis in two families (PMID: 19504606). ClinVar contains an entry for this variant (Variation ID: 381658). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

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