10-62813496-C-T

Variant names:

• chr10-62813496-C-T
• rs281865137
• NM_000399.5:c.1142G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000399.5(EGR2):​c.1142G>A​(p.Arg381His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R381L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EGR2 NM_000399.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 U:3 O:1
• Conservation: PhyloP100: 7.89
• Publications: 16 publications found

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]

EGR2 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease type 4E

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• Charcot-Marie-Tooth disease

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease type 1D

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Charcot-Marie-Tooth disease type 3

  Inheritance: SD, AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 3 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 chr10-62813496-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1075624.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945
• PP5: Variant 10-62813496-C-T is Pathogenic according to our data. Variant chr10-62813496-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 41008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000399.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGR2	NM_000399.5	MANE Select	c.1142G>A	p.Arg381His	missense	Exon 2 of 2	NP_000390.2
	EGR2	NM_001410931.1		c.1181G>A	p.Arg394His	missense	Exon 3 of 3	NP_001397860.1
	EGR2	NM_001136177.3		c.1142G>A	p.Arg381His	missense	Exon 3 of 3	NP_001129649.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGR2	ENST00000242480.4	TSL:1 MANE Select	c.1142G>A	p.Arg381His	missense	Exon 2 of 2	ENSP00000242480.3
	EGR2	ENST00000439032.6	TSL:1	n.*1157G>A		non_coding_transcript_exon	Exon 2 of 2	ENSP00000509775.1
	EGR2	ENST00000439032.6	TSL:1	n.*1157G>A		3_prime_UTR	Exon 2 of 2	ENSP00000509775.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Uncertain:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease type 1D Pathogenic:1 Uncertain:1 Other:1

Dec 01, 2020

CMT Laboratory, Bogazici University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 06, 2016

Inherited Neuropathy Consortium Ii, University Of Miami

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

not provided Pathogenic:2

Aug 12, 2021

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was not reported in large, multi-ethnic, general populations (http://gnomad.broadinstitute.org). This variant appears to occur de novo in multiple individuals with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. Multiple studies have shown that this variant results in the loss of transcriptional regulatory activity required for normal myelination (PMID: 11734543, 12609493).

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

EGR2: PM1, PM2, PM5, PM6, PS4:Moderate, PS3:Supporting

Charcot-Marie-Tooth disease Uncertain:2

Inherited Neuropathy Consortium

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

Aug 14, 2019

Genesis Genome Database

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

Charcot-Marie-Tooth disease, type I Pathogenic:1

Jan 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 381 of the EGR2 protein (p.Arg381His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Charcot-Marie-Tooth (CMT) (PMID: 10762521, 12471219, 22765307, 25720245). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 41008). 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. Experimental studies have shown that this missense change affects EGR2 function (PMID: 12609493). This variant disrupts the p.Arg381 amino acid residue in EGR2. Other variant(s) that disrupt this residue have been observed in individuals with EGR2-related conditions (PMID: 11239949, 20513111), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.031	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		7.9
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.64
MutPred		0.93		Loss of MoRF binding (P = 0.0105)
MVP		0.88
MPC		2.2
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.80
gMVP		0.86
Mutation Taster		=8/92	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs281865137; hg19: chr10-64573256; COSMIC: COSV54346412; COSMIC: COSV54346412;