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

dbSNP: rs104894161

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000231023	SCV000284825	pathogenic	Charcot-Marie-Tooth disease, type I	2022-07-26	criteria provided, single submitter	clinical testing	Experimental studies have shown that this missense change affects EGR2 function (PMID: 10369870, 17717711). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 16752). This missense change has been observed in individual(s) with Dejerine-Sottas syndrome (DSS) or Charcot-Marie-Tooth disease type 1 (PMID: 10371530, 11523566, 15947997, 27159987). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 359 of the EGR2 protein (p.Arg359Trp). This variant disrupts the p.Arg359 amino acid residue in EGR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16198564). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000498897	SCV000589657	pathogenic	not provided	2021-12-07	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a reduced DNA binding affinity, altered DNA binding specificity and decreased transcriptional activity (Sevilla et al., 2015; Barrera et al., 2016; Warner et al., 1999); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10371530, 21840889, 15947997, 27013732, 26204789, 27159987, 16775366, 10369870)
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV000032120	SCV001150099	pathogenic	Dejerine-Sottas disease	2017-12-19	criteria provided, single submitter	clinical testing
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 type 1D	2005-09-01	no assertion criteria provided	literature only
GeneReviews	RCV000032120	SCV000055669	not provided	Dejerine-Sottas disease		no assertion provided	literature only
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
Inherited Neuropathy Consortium Ii, University Of Miami	RCV000032120	SCV004174374	uncertain significance	Dejerine-Sottas disease	2016-01-06	no assertion criteria provided	literature only