rs104894161

Positions:

• chr10-62813563-G-A
• chr10-62813563-G-C

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.1075C>T​(p.Arg359Trp) 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. R359G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EGR2 NM_000399.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 U:3 O:1
• Conservation: PhyloP100: -0.0920

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 1 (size 24) in uniprot entity EGR2_HUMAN there are 7 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 chr10-62813562-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 41007.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94
• PP5: Variant 10-62813563-G-A is Pathogenic according to our data. Variant chr10-62813563-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 16752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-62813563-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EGR2	NM_000399.5	c.1075C>T	p.Arg359Trp	missense_variant	2/2	ENST00000242480.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EGR2	ENST00000242480.4	c.1075C>T	p.Arg359Trp	missense_variant	2/2	1	NM_000399.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Uncertain:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dejerine-Sottas disease Pathogenic:1 Uncertain:2 Other:1

Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium	-	- -
Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium Ii, University Of Miami	Jan 06, 2016	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Dec 19, 2017	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 2021	Published functional studies demonstrate a reduced DNA binding affinity, altered DNA binding specificity and decreased transcriptional activity (Sevilla et al., 2015; Barrera et al., 2016; Warner et al., 1999); Not observed at significant frequency in large population cohorts (gnomAD); 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: 10371530, 21840889, 15947997, 27013732, 26204789, 27159987, 16775366, 10369870) -

Dejerine-sottas neuropathy, autosomal dominant Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2005

- -

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2005

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 26, 2022

Experimental studies have shown that this missense change affects EGR2 function (PMID: 10369870, 17717711). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 16752). This missense change has been observed in individual(s) with Dejerine-Sottas syndrome (DSS) or Charcot-Marie-Tooth disease type 1 (PMID: 10371530, 11523566, 15947997, 27159987). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 359 of the EGR2 protein (p.Arg359Trp). This variant disrupts the p.Arg359 amino acid residue in EGR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16198564). 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. -

Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, no assertion criteria provided

research

Genesis Genome Database

Aug 14, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D;.;D
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.77	.;T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.8	M;.;M
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-7.5	D;D;D
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.87
MutPred		0.87		Loss of disorder (P = 8e-04);.;Loss of disorder (P = 8e-04);
MVP		0.86
MPC		2.0
ClinPred		0.99	D
GERP RS		-4.7
Varity_R		0.80
gMVP		0.92

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: rs104894161; hg19: chr10-64573323;