ClinVar Miner

Submissions for variant NM_000399.5(EGR2):c.832G>A (p.Ala278Thr) (rs565355765)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000761723 SCV000621425 uncertain significance not provided 2017-10-06 criteria provided, single submitter clinical testing The A278T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The A278T variant is observed in 25/30,772 (0.08%) alleles from individuals of South Asian background (Lek et al., 2016). The A278T 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 likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000761723 SCV000891908 likely benign not provided 2018-05-01 criteria provided, single submitter clinical testing
Invitae RCV001040079 SCV001203634 uncertain significance Charcot-Marie-Tooth disease, type I 2020-06-23 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 278 of the EGR2 protein (p.Ala278Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs565355765, ExAC 0.07%). This variant has not been reported in the literature in individuals with EGR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 452606). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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