rs864622273

chr10-62813412-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP3 PP5_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:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: EGR2 NM_000399.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.91

Genes affected

EGR2 (HGNC:3239): (early growth response 2) The protein encoded by this gene is a transcription factor with three tandem C2H2-type zinc fingers. Defects in this gene are associated with Charcot-Marie-Tooth disease type 1D (CMT1D), Charcot-Marie-Tooth disease type 4E (CMT4E), and with Dejerine-Sottas syndrome (DSS). Multiple transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000399.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-62813413-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 16750.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.791
• PP5: Variant 10-62813412-C-T is Pathogenic according to our data. Variant chr10-62813412-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 219844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-62813412-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EGR2	NM_000399.5	c.1226G>A	p.Arg409Gln	missense_variant	2/2	ENST00000242480.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EGR2	ENST00000242480.4	c.1226G>A	p.Arg409Gln	missense_variant	2/2	1	NM_000399.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251058 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135642

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461340 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726868

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

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

Invitae

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.33
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D;.;D
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.019	T
MetaRNN	Pathogenic	0.79	D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.73	N;.;N
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.6	D;D;D
REVEL	Uncertain	0.36
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		0.99	D;D;D
Vest4		0.69
MutPred		0.73		Loss of MoRF binding (P = 0.0291);.;Loss of MoRF binding (P = 0.0291);
MVP		0.63
MPC		2.0
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.85
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs864622273; hg19: chr10-64573172; COSMIC: COSV54346929; COSMIC: COSV54346929;