Submissions for variant NM_000399.5(EGR2):c.457A>C (p.Thr153Pro)

gnomAD frequency: 0.00018  dbSNP: rs202183386

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000540413	SCV000636230	likely benign	Charcot-Marie-Tooth disease, type I	2025-01-15	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001108766	SCV001266038	likely benign	Charcot-Marie-Tooth disease type 1D	2018-01-13	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.
Ambry Genetics	RCV002341304	SCV002636234	uncertain significance	Inborn genetic diseases	2019-09-09	criteria provided, single submitter	clinical testing	The p.T153P variant (also known as c.457A>C), located in coding exon 2 of the EGR2 gene, results from an A to C substitution at nucleotide position 457. The threonine at codon 153 is replaced by proline, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Given the population frequency of this alteration, it is unlikely to cause dominant disease; however its pathogenicity for recessive disease is unknown. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear for autosomal recessive disease.
CeGaT Center for Human Genetics Tuebingen	RCV001356784	SCV004700946	uncertain significance	not provided	2024-01-01	criteria provided, single submitter	clinical testing	EGR2: PM2
Fulgent Genetics, Fulgent Genetics	RCV005044805	SCV005682539	uncertain significance	Charcot-Marie-Tooth disease type 1D; Dejerine-Sottas disease; Charcot-Marie-Tooth disease type 4E	2024-01-29	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356784	SCV001552046	uncertain significance	not provided		no assertion criteria provided	clinical testing	The EGR2 p.Thr103Pro variant was not identified in the literature but was identified in dbSNP (ID: rs202183386) and ClinVar (classified as likely benign by Invitae). The variant was identified in control databases in 53 of 282632 chromosomes at a frequency of 0.0001875 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 41 of 10358 chromosomes (freq: 0.003958), Other in 1 of 7216 chromosomes (freq: 0.000139), European (non-Finnish) in 10 of 129006 chromosomes (freq: 0.000078) and African in 1 of 24938 chromosomes (freq: 0.00004), but was not observed in the Latino, East Asian, European (Finnish), or South Asian populations. The p.Thr103 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.