rs864622273
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_Strong
The NM_000399.5(EGR2):c.1226G>A(p.Arg409Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R409W) has been classified as Pathogenic.
Frequency
Consequence
NM_000399.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
EGR2 | NM_000399.5 | c.1226G>A | p.Arg409Gln | missense_variant | 2/2 | ENST00000242480.4 | NP_000390.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
EGR2 | ENST00000242480.4 | c.1226G>A | p.Arg409Gln | missense_variant | 2/2 | 1 | NM_000399.5 | ENSP00000242480 | A1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251058Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135642
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461340Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726868
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not specified Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jul 25, 2018 | The p.Arg409Gln variant (rs864622273) was observed segregating with CMT-affected individuals in a multi-generation family (Sevilla 2015). The same arginine residue changed to a tryptophan was also shown segregating with CMT disease in a different family (Warner 1998). The p.Arg409Gln is absent from general population databases such as 1000 Genomes, NHLBI GO Exome Sequencing Project (ESP), and the Genome Aggregation Database (gnomAD), and has been reported to the ClinVar database as a pathogenic/likely pathogenic variant (ClinVar ID: 219844). The arginine at position 409 is highly conserved in the animal kingdom and is located in the third zinc-finger domain of the EGR2, which is required for DNA binding and specificity. More importantly this variant is clustered with other disease causing variants that are observed in the three zinc finger domains of EGR2 listed in HGMD (Stenson 2017 and Alamut v2.10). Functional studies also support a reduction in transcriptional activity of the p.Arg409Gln variant compared to wild type (Sevilla 2015). Given the current evidence, this variant is likely to be pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 11, 2020 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 26263471, 26204789, 30843326) - |
Charcot-Marie-Tooth disease, type I Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 11, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 409 of the EGR2 protein (p.Arg409Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with autosomal dominant Charcot-Marie-Tooth disease (PMID: 26204789; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 219844). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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: 26204789). 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: 9537424, 17717711, 27013732). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at