rs104894159

Variant names:

• chr10-62813413-G-A
• rs104894159
• NM_000399.5:c.1225C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000399.5(EGR2):​c.1225C>T​(p.Arg409Trp) variant causes a missense change involving the alteration of a non-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. R409Q) 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:3 U:1 O:1
• Conservation: PhyloP100: 0.676

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 18 ACMG points.

• PM1: In a zinc_finger_region C2H2-type 3 (size 22) in uniprot entity EGR2_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) 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 chr10-62813412-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94
• PP5: Variant 10-62813413-G-A is Pathogenic according to our data. 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. Variant chr10-62813413-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGR2	NM_000399.5	c.1225C>T	p.Arg409Trp	missense_variant	Exon 2 of 2	ENST00000242480.4	NP_000390.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EGR2	ENST00000242480.4	c.1225C>T	p.Arg409Trp	missense_variant	Exon 2 of 2	1	NM_000399.5	ENSP00000242480.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

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

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jan 14, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jan 06, 2016

Inherited Neuropathy Consortium Ii, University Of Miami

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Apr 21, 2023

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been identified in at least one individual with clinical features associated with this CMT. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In some published literature, this variant is referred to as R359W. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 10369870, 26204789) The variant is located in a region that is considered important for protein function and/or structure. -

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

Nov 03, 2024

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 tryptophan, which is neutral and slightly polar, at codon 409 of the EGR2 protein (p.Arg409Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant Charcot-Marie-Tooth disease (CMT) (PMID: 9537424, 30481651). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16750). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 10369870, 26204789, 27013732). 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: 26204789; internal data). 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	1.0
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;.;D
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.95	.;D;D
M_CAP	Benign	0.021	T
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.70	N;.;N
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-7.2	D;D;D
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.77
MutPred		0.86		Loss of disorder (P = 0.0081);.;Loss of disorder (P = 0.0081);
MVP		0.85
MPC		2.0
ClinPred		1.0	D
GERP RS		3.0
Varity_R		0.86
gMVP		0.94

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: rs104894159; hg19: chr10-64573173;