VCV000016752.17 - ClinVar

NM_000399.5(EGR2):c.1075C>T (p.Arg359Trp)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(10)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000399.5(EGR2):c.1075C>T (p.Arg359Trp)

Variation ID: 16752 Accession: VCV000016752.17

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q21.3 10: 62813563 (GRCh38) [ NCBI UCSC ] 10: 64573323 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Sep 16, 2024	Jul 26, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000399.5:c.1075C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000390.2:p.Arg359Trp	missense
NM_001136177.3:c.1075C>T	NP_001129649.1:p.Arg359Trp	missense
NM_001136178.2:c.1075C>T	NP_001129650.1:p.Arg359Trp	missense
NM_001136179.3:c.925C>T	NP_001129651.1:p.Arg309Trp	missense
NM_001321037.2:c.925C>T	NP_001307966.1:p.Arg309Trp	missense
NC_000010.11:g.62813563G>A
NC_000010.10:g.64573323G>A
NG_008936.2:g.111338C>T
LRG_239:g.111338C>T
LRG_239t1:c.1075C>T
	P11161:p.Arg359Trp

... more HGVS ... less HGVS

Protein change

R359W, R309W

Other names

Canonical SPDI

NC_000010.11:62813562:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA126845 UniProtKB: P11161#VAR_009874 OMIM: 129010.0004 dbSNP: rs104894161 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
EGR2		No evidence available	No evidence available	GRCh38 GRCh37	400	424

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Dejerine-sottas neuropathy, autosomal dominant	Pathogenic (1)	no assertion criteria provided	Sep 1, 2005	RCV000018236.28
Charcot-Marie-Tooth disease type 1D	Pathogenic (1)	no assertion criteria provided	Sep 1, 2005	RCV000018237.24
Dejerine-Sottas disease	Pathogenic (4)	criteria provided, single submitter	Dec 19, 2017	RCV000032120.11
Charcot-Marie-Tooth disease, type I	Pathogenic (1)	criteria provided, single submitter	Jul 26, 2022	RCV000231023.6
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Dec 7, 2021	RCV000498897.6
Charcot-Marie-Tooth disease	Uncertain significance (1)	no assertion criteria provided	Aug 14, 2019	RCV000856959.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Dec 07, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000589657.5 First in ClinVar: Aug 20, 2017 Last updated: Mar 04, 2023	Comment: 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; … (more) 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) (less)
Pathogenic (Jul 26, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Charcot-Marie-Tooth disease, type I Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000284825.6 First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024	Publications: PubMed (7) PubMed: 10369870‚ 17717711‚ 10371530‚ 11523566‚ 15947997‚ 27159987‚ 16198564 Comment: 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 … (more) 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. (less)
Pathogenic (Dec 19, 2017)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Dejerine-Sottas disease (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV001150099.1 First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020	Sex: male Tissue: blood
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Unknown mechanism) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001447847.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Polyneuropathy (present) , Muscle weakness (present) Sex: male
Pathogenic (Sep 01, 2005)	no assertion criteria provided Method: literature only	DEJERINE-SOTTAS NEUROPATHY, AUTOSOMAL DOMINANT Affected status: not provided Allele origin: germline	OMIM Accession: SCV000038515.2 First in ClinVar: Apr 04, 2013 Last updated: Sep 16, 2024	Publications: PubMed (3) PubMed: 11523566‚ 15947997‚ 10369870 Comment on evidence: Dejerine-Sottas Neuropathy Boerkoel et al. (2001) reported 2 patients with Dejerine-Sottas neuropathy (145900) and an arg359-to-trp (R359W) mutation in the EGR2 gene. In both patients, … (more) Dejerine-Sottas Neuropathy Boerkoel et al. (2001) reported 2 patients with Dejerine-Sottas neuropathy (145900) and an arg359-to-trp (R359W) mutation in the EGR2 gene. In both patients, the mutation appeared to be de novo dominant. One patient presented with hypotonia and hip dysplasia immediately after birth. She gained minimal use of her hands and feet during the first 6 months of life and then gradually lost motor function, developing paralysis distal to the knees and elbows by 2 years of age. A sural nerve biopsy demonstrated a marked decrease of myelinated fibers, evidence of demyelination and remyelination, and onion bulb formation. The course of her disease was characterized by increasing difficulty swallowing and breathing, and she died of respiratory failure at 6 years of age. The other patient had difficulty grasping objects and strabismus secondary to lateral recti weakness by 4 to 5 months of age. At 3 years of age, she had severe distal muscle weakness and atrophy, areflexia, and decreased pain and temperature sensation; in the lower extremities, she had less severe distal muscle weakness and atrophy, hyporeflexia, and intact sensation. As a complication of her hand involvement, she developed bilateral fixed contractures of the fourth and fifth fingers by 15 years of age. At 3 years of age nerve conduction velocities could not be measured in the median and ulnar nerve, but tibial nerve conduction velocity was 8 m/s. Sural nerve biopsy showed typical changes of DSN, including onion bulb formation. She developed severe thoracolumbar scoliosis, requiring spinal fusion at 15 years of age. At age 22 years she was following a rigorous physical exercise program, including weight lifting and walking on a treadmill, and she had completed a university education. Charcot-Marie-Tooth Disease, Demyelinating, Type 1D Chung et al. (2005) identified a heterozygous R359W mutation in the ERG2 gene in a Korean father with Charcot-Marie-Tooth disease type 1D (CMT1D; 607678) and a daughter with Dejerine-Sottas syndrome. In addition, the daughter was found to have a de novo mutation in the GJB1 gene (V136A; 304040.0021). The father had pes cavus and developed difficulty walking at age 8 years, but had a milder phenotype than the daughter, who had experienced gait difficulties since infancy and facial weakness. She also had bilateral hand muscle weakness and atrophy and had sensory impairment of both upper and lower extremities. Warner et al. (1999) had shown that the R359W substitution occurs in the first zinc finger domain and results in very low DNA-binding activity as well as decreased transcriptional activity of GJB1, resulting in abnormal myelination. Chung et al. (2005) concluded that the more severe phenotype in the daughter was caused by an additive effect of the 2 mutations. (less)
Pathogenic (Sep 01, 2005)	no assertion criteria provided Method: literature only	CHARCOT-MARIE-TOOTH DISEASE, DEMYELINATING, TYPE 1D Affected status: not provided Allele origin: germline	OMIM Accession: SCV005205537.1 First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024	Publications: PubMed (3) PubMed: 11523566‚ 15947997‚ 10369870 Comment on evidence: Dejerine-Sottas Neuropathy Boerkoel et al. (2001) reported 2 patients with Dejerine-Sottas neuropathy (145900) and an arg359-to-trp (R359W) mutation in the EGR2 gene. In both patients, … (more) Dejerine-Sottas Neuropathy Boerkoel et al. (2001) reported 2 patients with Dejerine-Sottas neuropathy (145900) and an arg359-to-trp (R359W) mutation in the EGR2 gene. In both patients, the mutation appeared to be de novo dominant. One patient presented with hypotonia and hip dysplasia immediately after birth. She gained minimal use of her hands and feet during the first 6 months of life and then gradually lost motor function, developing paralysis distal to the knees and elbows by 2 years of age. A sural nerve biopsy demonstrated a marked decrease of myelinated fibers, evidence of demyelination and remyelination, and onion bulb formation. The course of her disease was characterized by increasing difficulty swallowing and breathing, and she died of respiratory failure at 6 years of age. The other patient had difficulty grasping objects and strabismus secondary to lateral recti weakness by 4 to 5 months of age. At 3 years of age, she had severe distal muscle weakness and atrophy, areflexia, and decreased pain and temperature sensation; in the lower extremities, she had less severe distal muscle weakness and atrophy, hyporeflexia, and intact sensation. As a complication of her hand involvement, she developed bilateral fixed contractures of the fourth and fifth fingers by 15 years of age. At 3 years of age nerve conduction velocities could not be measured in the median and ulnar nerve, but tibial nerve conduction velocity was 8 m/s. Sural nerve biopsy showed typical changes of DSN, including onion bulb formation. She developed severe thoracolumbar scoliosis, requiring spinal fusion at 15 years of age. At age 22 years she was following a rigorous physical exercise program, including weight lifting and walking on a treadmill, and she had completed a university education. Charcot-Marie-Tooth Disease, Demyelinating, Type 1D Chung et al. (2005) identified a heterozygous R359W mutation in the ERG2 gene in a Korean father with Charcot-Marie-Tooth disease type 1D (CMT1D; 607678) and a daughter with Dejerine-Sottas syndrome. In addition, the daughter was found to have a de novo mutation in the GJB1 gene (V136A; 304040.0021). The father had pes cavus and developed difficulty walking at age 8 years, but had a milder phenotype than the daughter, who had experienced gait difficulties since infancy and facial weakness. She also had bilateral hand muscle weakness and atrophy and had sensory impairment of both upper and lower extremities. Warner et al. (1999) had shown that the R359W substitution occurs in the first zinc finger domain and results in very low DNA-binding activity as well as decreased transcriptional activity of GJB1, resulting in abnormal myelination. Chung et al. (2005) concluded that the more severe phenotype in the daughter was caused by an additive effect of the 2 mutations. (less)
Uncertain significance (-)	no assertion criteria provided Method: literature only	Dejerine-Sottas disease Affected status: yes Allele origin: germline	Inherited Neuropathy Consortium Accession: SCV000929126.1 First in ClinVar: Jul 29, 2019 Last updated: Jul 29, 2019	Publications: PubMed (1) PubMed: 15947997
Uncertain significance (Aug 14, 2019)	no assertion criteria provided Method: research	Charcot-Marie-Tooth disease Affected status: yes Allele origin: germline	Genesis Genome Database Accession: SCV000999524.1 First in ClinVar: Dec 06, 2019 Last updated: Dec 06, 2019
Uncertain significance (Jan 06, 2016)	no assertion criteria provided Method: literature only	Dejerine-Sottas disease Affected status: yes Allele origin: germline	Inherited Neuropathy Consortium Ii, University Of Miami Accession: SCV004174374.1 First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023	Publications: PubMed (1) PubMed: 15947997
not provided (-)	no classification provided Method: literature only	Dejerine-Sottas disease Affected status: not provided Allele origin: unknown	GeneReviews Accession: SCV000055669.2 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022	Publications: PubMed (1) PubMed: 20301384 BookShelf: NBK1205 BookShelf: NBK1205

Comment:

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)

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
EGR2 mutation enhances phenotype spectrum of Dejerine-Sottas syndrome.	Gargaun E	Journal of neurology	2016	PMID: 27159987
Charcot-Marie-Tooth Neuropathy Type 1 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.	Adam MP	-	2015	PMID: 20301384
Functional, histopathologic and natural history study of neuropathy associated with EGR2 mutations.	Szigeti K	Neurogenetics	2007	PMID: 17717711
Novel EGR2 mutation R359Q is associated with CMT type 1 and progressive scoliosis.	Mikesová E	Neuromuscular disorders : NMD	2005	PMID: 16198564
Two missense mutations of EGR2 R359W and GJB1 V136A in a Charcot-Marie-Tooth disease family.	Chung KW	Neurogenetics	2005	PMID: 15947997
EGR2 mutation R359W causes a spectrum of Dejerine-Sottas neuropathy.	Boerkoel CF	Neurogenetics	2001	PMID: 11523566
Novel missense mutation in the early growth response 2 gene associated with Dejerine-Sottas syndrome phenotype.	Timmerman V	Neurology	1999	PMID: 10371530
Functional consequences of mutations in the early growth response 2 gene (EGR2) correlate with severity of human myelinopathies.	Warner LE	Human molecular genetics	1999	PMID: 10369870

Text-mined citations for rs104894161 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000399.5(EGR2):c.1075C>T (p.Arg359Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs104894161 ...