NM_000399.5(EGR2):c.1225C>T (p.Arg409Trp) AND Charcot-Marie-Tooth disease, type I

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Aug 1, 2020
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001049422.8

Allele description [Variation Report for NM_000399.5(EGR2):c.1225C>T (p.Arg409Trp)]

NM_000399.5(EGR2):c.1225C>T (p.Arg409Trp)

Gene:

EGR2:early growth response 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q21.3

Genomic location:

Preferred name:

NM_000399.5(EGR2):c.1225C>T (p.Arg409Trp)

HGVS:

NC_000010.11:g.62813413G>A
NG_008936.2:g.111488C>T
NM_000399.4:c.1225C>T
NM_000399.5:c.1225C>TMANE SELECT
NM_001136177.3:c.1225C>T
NM_001136178.2:c.1225C>T
NM_001136179.3:c.1075C>T
NM_001321037.2:c.1075C>T
NP_000390.2:p.Arg409Trp
NP_001129649.1:p.Arg409Trp
NP_001129650.1:p.Arg409Trp
NP_001129651.1:p.Arg359Trp
NP_001307966.1:p.Arg359Trp
LRG_239t1:c.1225C>T
LRG_239:g.111488C>T
NC_000010.10:g.64573173G>A
NM_000399.3:c.1225C>T
P11161:p.Arg409Trp

Protein change:

R359W; ARG409TRP

Links:

UniProtKB: P11161#VAR_007738; OMIM: 129010.0002; dbSNP: rs104894159

NCBI 1000 Genomes Browser:

rs104894159

Molecular consequence:

NM_000399.5:c.1225C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001136177.3:c.1225C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001136178.2:c.1225C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001136179.3:c.1075C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001321037.2:c.1075C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Charcot-Marie-Tooth disease, type I (CMT1)
Synonyms:: Charcot-Marie-Tooth Neuropathy Type 1; Hereditary Motor and Sensory Neuropathy 1; Charcot-Marie-Tooth, Type 1
Identifiers:: MONDO: MONDO:0019011; MedGen: C0751036

Recent activity

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Homo sapiens glycosylphosphatidylinositol anchored molecule like (GML), mRNA
Homo sapiens glycosylphosphatidylinositol anchored molecule like (GML), mRNA
gi|169646780|ref|NM_002066.2|

Nucleotide
Trim75 tripartite motif-containing 75 [Mus musculus]
Trim75 tripartite motif-containing 75 [Mus musculus]
Gene ID:333307

Gene
333307[uid] AND (alive[prop]) (1)
Gene
LMBR1 domain containing 1 [Mus musculus]
LMBR1 domain containing 1 [Mus musculus]
gi|19343769|gb|AAH25579.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001213471	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 1, 2020)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 9537424, 30481651, 10369870, 26204789, 27013732, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001213471

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 1, 2020)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations in the early growth response 2 (EGR2) gene are associated with hereditary myelinopathies.

Warner LE, Mancias P, Butler IJ, McDonald CM, Keppen L, Koob KG, Lupski JR.

Nat Genet. 1998 Apr;18(4):382-4.

PubMed [citation]

PMID:: 9537424

Widening the phenotypical spectrum of EGR2-related CMT: Unusual phenotype for R409W mutation.

Leonardi L, Garibaldi M, Fionda L, Vanoli F, Loreti S, Morino S, Antonini G.

Clin Neurophysiol. 2019 Jan;130(1):93-94. doi: 10.1016/j.clinph.2018.11.007. Epub 2018 Nov 22. No abstract available.

PubMed [citation]

PMID:: 30481651

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001213471.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

For these reasons, this variant has been classified as Pathogenic. 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, Invitae). This suggests that this residue is clinically-significant, and that variants that disrupt this residue are likely to be disease-causing. This sequence change replaces arginine with tryptophan at codon 409 of the EGR2 protein (p.Arg409Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with¬†Charcot-Marie-Tooth disease (CMT) and to segregate with CMT in a family (PMID: 9537424, 30481651). ClinVar contains an entry for this variant (Variation ID: 16750). This variant has been reported to affect EGR2 protein function (PMID: 10369870, 26204789, 27013732).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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