Submissions for variant NM_000399.5(EGR2):c.644C>T (p.Thr215Met)

gnomAD frequency: 0.00039  dbSNP: rs139147487

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000858272	SCV000293292	uncertain significance	not provided	2023-08-08	criteria provided, single submitter	clinical testing	Reported previously as a variant of uncertain significance in two patients with suspected CMT; however, no further clinical or segregation information was provided (Volodarsky et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32376792)
Invitae	RCV000236817	SCV000294218	likely benign	Charcot-Marie-Tooth disease, type I	2024-01-18	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001094002	SCV000363336	likely benign	Charcot-Marie-Tooth disease type 1D	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
CeGaT Center for Human Genetics Tuebingen	RCV000858272	SCV001147910	uncertain significance	not provided	2016-11-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002365227	SCV002659633	likely benign	Inborn genetic diseases	2019-11-01	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
PreventionGenetics, part of Exact Sciences	RCV003955388	SCV004773629	uncertain significance	EGR2-related condition	2023-12-20	criteria provided, single submitter	clinical testing	The EGR2 c.644C>T variant is predicted to result in the amino acid substitution p.Thr215Met. This variant was reported in two individuals from a Charcot-Marie-Tooth disease cohort (Supplementary Table 2 in Volodarsky et al. 2021. PubMed ID: 32376792). This variant is reported in 0.11% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which may be too frequent for a disease-causing variant in EGR2. This variant has conflicting interpretations in ClinVar ranging from uncertain to likely benign (https://preview.ncbi.nlm.nih.gov/clinvar/variation/246013/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.