ClinVar Miner

Submissions for variant NM_001399.5(EDA):c.794A>G (p.Asp265Gly) (rs727504750)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000156051 SCV000205764 uncertain significance not specified 2013-10-31 criteria provided, single submitter clinical testing The Asp265Gly variant in EDA has not been previously reported in individuals wit h ectodermal dysplasia or in large population studies. A different amino acid ch ange at this position (Arg265Asn) has been seen in one individual with clinical features of ectodermal dysplasia by our laboratory, but it is unclear if that va riant was the cause of the clinical features. The aspartic acid (Asp) residue at position 265 is highly conserved across mammals and evolutionarily distant spec ies, suggesting that a change to the amino acid may not be tolerated. In additio n, computational analyses (biochemical amino acid properties, AlignGVGD, PolyPhe n2, and SIFT) suggest that the Asp265Gly variant may impact the protein. Alterna tively, although this variant is located in the first base of the exon, which is part of the 5? splice consensus region, computational tools do not predict alte red splicing. However, the accuracy of these predicative tools is unknown and th erefore, not predictive enough to assume or rule out pathogenicity. In summary, additional information is needed to fully assess the clinical significance of th e Asp265Gly variant.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000156051 SCV000603412 likely pathogenic not specified 2016-09-07 criteria provided, single submitter clinical testing
Invitae RCV000796602 SCV000936122 pathogenic Hypohidrotic X-linked ectodermal dysplasia 2019-06-19 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 265 of the EDA protein (p.Asp265Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with hypohidrotic ectodermal dysplasia (PMID: 25333067). It has also been observed to segregate with clinical features of hypohidrotic ectodermal dysplasia in a family (Invitae). ClinVar contains an entry for this variant (Variation ID: 179264). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.

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