ClinVar Miner

Submissions for variant NM_000399.5(EGR2):c.1075C>T (p.Arg359Trp) (rs104894161)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000498897 SCV000589657 pathogenic not provided 2019-01-14 criteria provided, single submitter clinical testing The R359W variant in the EGR2 gene has been reported previously in the heterozygous state in multiple, unrelated individuals with Dejerine-Sottas neuropathy or CMT1D (Timmerman et al., 1999; Gargaun et al., 2016; Chung et al., 2005). The R359W variant is located within zinc finger 1 domain and functional studies demonstrate that R359W has reduced DNA binding affinity, altered DNA binding specificity and decreased transcriptional activity (Sevilla et al., 2015; Barrera et al., 2016). The R359W variant is not observed in large population cohorts (Lek et al., 2016). The R359W 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. We interpret R359W as a pathogenic variant.
GeneReviews RCV000032120 SCV000055669 pathologic Dejerine-Sottas disease 2012-10-18 no assertion criteria provided curation Converted during submission to Pathogenic.
Inherited Neuropathy Consortium RCV000032120 SCV000929126 uncertain significance Dejerine-Sottas disease no assertion criteria provided literature only
Invitae RCV000231023 SCV000284825 pathogenic Charcot-Marie-Tooth disease, type I 2017-08-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 359 of the EGR2 protein (p.Arg359Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with Dejerine-Sottas syndrome (DSS) and one individual affected with Charcot-Marie-Tooth disease type 1 (PMID: 10371530, 11523566, 15947997). In several of the individuals affected with DSS, this variant is likely to have arisen de novo; however, paternity was not tested (PMID: 10371530, 11523566, 27159987). ClinVar contains an entry for this variant (Variation ID: 16752) EGR2 encodes a transcription factor, and experimental studies have shown that this missense change disrupts its DNA binding and transactivation activity (PMID: 10369870, 17717711). A different missense substitution at this codon (p.Arg359Gln) has been reported to be deleterious (PMID: 16198564), which also suggests that the arginine residue is important for EGR2 protein function. In summary, this is a rare missense change that has been reported in multiple affected individuals and is likely a recurrent de novo mutation. In addition, experimental evidence indicates that it disrupts EGR2 protein function. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000018236 SCV000038515 pathogenic Dejerine-sottas neuropathy, autosomal dominant 2005-09-01 no assertion criteria provided literature only
OMIM RCV000018237 SCV000038516 pathogenic Charcot-Marie-Tooth disease, demyelinating, type 1d 2005-09-01 no assertion criteria provided literature only

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