ClinVar Miner

Submissions for variant NM_000399.5(EGR2):c.1226G>A (p.Arg409Gln) (rs864622273)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000206846 SCV000259942 pathogenic Charcot-Marie-Tooth disease, type I 2020-07-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 409 of the EGR2 protein (p.Arg409Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with autosomal dominant Charcot-Marie-Tooth disease in a family (PMID: 26204789) and has been reported in an individual affected with Charcot-Marie-Tooth disease (Invitae). ClinVar contains an entry for this variant (Variation ID: 219844). Experimental studies have shown that this missense change detrimentally affects the DNA-binding function of the EGR2 protein (PMID: 26204789). A different missense substitution at this codon (p.Arg409Trp) has been determined to be pathogenic (PMID: 17717711, 9537424, 27013732,9537424). This suggests that the arginine residue is critical for EGR2 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000431412 SCV000525092 likely pathogenic not provided 2016-10-28 criteria provided, single submitter clinical testing A variant that is likely pathogenic has been identified in the EGR2 gene. The R409Q missense variant has been reported previously in family members with axonal Charcot-Marie-Tooth disease presenting in adulthood (Sevilla et al., 2015). Additionally, R409Q is reported as a pathogenic variant in ClinVar by a different clinical laboratory, but additional evidence is not available (ClinVar SCV000259942.1; Landrum et al., 2016). Functional studies show that this variant impacts the EGR2 protein by reducing its transcriptional activity (Sevilla et al., 2015). The R409Q variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In silico analysis predicts the R409Q variant is probably damaging to the protein structure/function. This substitution alters a conserved position predicted to be within the third zinc-finger domain (Sevilla et al., 2015). A different missense variant at the same codon (R409W) as well as two missense variants in a nearby residue (E412K and E412G) have also been reported in the Human Gene Mutation Database in association with EGR2-related disorders (Stenson et al., 2014). Therefore, the R409Q variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000999872 SCV000883780 likely pathogenic not specified 2018-07-25 criteria provided, single submitter clinical testing The p.Arg409Gln variant (rs864622273) was observed segregating with CMT-affected individuals in a multi-generation family (Sevilla 2015). The same arginine residue changed to a tryptophan was also shown segregating with CMT disease in a different family (Warner 1998). The p.Arg409Gln is absent from general population databases such as 1000 Genomes, NHLBI GO Exome Sequencing Project (ESP), and the Genome Aggregation Database (gnomAD), and has been reported to the ClinVar database as a pathogenic/likely pathogenic variant (ClinVar ID: 219844). The arginine at position 409 is highly conserved in the animal kingdom and is located in the third zinc-finger domain of the EGR2, which is required for DNA binding and specificity. More importantly this variant is clustered with other disease causing variants that are observed in the three zinc finger domains of EGR2 listed in HGMD (Stenson 2017 and Alamut v2.10). Functional studies also support a reduction in transcriptional activity of the p.Arg409Gln variant compared to wild type (Sevilla 2015). Given the current evidence, this variant is likely to be pathogenic.

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