ClinVar Miner

Submissions for variant NM_021008.4(DEAF1):c.716A>G (p.Glu239Gly)

gnomAD frequency: 0.00001  dbSNP: rs1064795812
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000482280 SCV000571974 uncertain significance not provided 2016-10-20 criteria provided, single submitter clinical testing The E239G variant in the DEAF1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The E239G variant was not observed in approximately 6500 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 E239G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret E239G as a variant of uncertain significance.
Mendelics RCV001171488 SCV001138198 uncertain significance Intellectual disability-epilepsy-extrapyramidal syndrome 2024-05-23 criteria provided, single submitter clinical testing This substitution has been reported in the medical literature in compound heterozygosity with a nonsense variant in a single individual presenting a neurodevelopmental phenotype. Functional studies performed did not disclose a functional impact for this mutant (no change in transcriptional repression activity or in transcriptional activation of the Eif4g3 promoter, normal localization to the nucleus) (PMID: 30923367). Although this variant might be possibly related to the patient’s phenotype, at this time evidence to confirm this is lacking, and therefore it has been considered of unknown significance.
Invitae RCV000482280 SCV002257912 likely pathogenic not provided 2021-01-29 criteria provided, single submitter clinical testing Experimental studies have shown that this variant does not substantially affect DEAF1 protein function (PMID: 30923367). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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) performed at Invitae indicates that this missense variant is expected to disrupt DEAF1 protein function. This variant has been observed in individual(s) with DEAF1-related conditions (PMID: 30923367). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 422488). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with glycine at codon 239 of the DEAF1 protein (p.Glu239Gly). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and glycine.
OMIM RCV001171488 SCV001334290 pathogenic Intellectual disability-epilepsy-extrapyramidal syndrome 2020-06-01 no assertion criteria provided literature only

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