ClinVar Miner

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

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000498897 SCV001447847 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
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
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
Genesis Genome Database RCV000856959 SCV000999524 uncertain significance Charcot-Marie-Tooth disease 2019-08-14 no assertion criteria provided research
Institute of Human Genetics, Klinikum rechts der Isar RCV000032120 SCV001150099 pathogenic Dejerine-Sottas disease 2017-12-19 no assertion criteria provided clinical testing

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