Submissions for variant NM_000399.5(EGR2):c.1225C>T (p.Arg409Trp)

dbSNP: rs104894159

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001049422	SCV001213471	pathogenic	Charcot-Marie-Tooth disease, type I	2024-11-03	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 409 of the EGR2 protein (p.Arg409Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant Charcot-Marie-Tooth disease (CMT) (PMID: 9537424, 30481651). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16750). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt EGR2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects EGR2 function (PMID: 10369870, 26204789, 27013732). This variant disrupts the p.Arg409 amino acid residue in EGR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26204789; internal data). 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.
Athena Diagnostics	RCV003482227	SCV004229623	pathogenic	not provided	2023-04-21	criteria provided, single submitter	clinical testing	This variant has been identified in at least one individual with clinical features associated with this CMT. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In some published literature, this variant is referred to as R359W. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 10369870, 26204789) The variant is located in a region that is considered important for protein function and/or structure.
OMIM	RCV000018234	SCV000038513	pathogenic	Charcot-Marie-Tooth disease type 1D	2003-01-14	no assertion criteria provided	literature only
GeneReviews	RCV000018234	SCV000055672	not provided	Charcot-Marie-Tooth disease type 1D		no assertion provided	literature only
Inherited Neuropathy Consortium Ii, University Of Miami	RCV000018234	SCV004174375	uncertain significance	Charcot-Marie-Tooth disease type 1D	2016-01-06	no assertion criteria provided	literature only