NM_000399.5(EGR2):c.670C>A (p.Pro224Thr) AND Charcot-Marie-Tooth disease, type I

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 26, 2023
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:: RCV000701472.9

Allele description [Variation Report for NM_000399.5(EGR2):c.670C>A (p.Pro224Thr)]

NM_000399.5(EGR2):c.670C>A (p.Pro224Thr)

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.670C>A (p.Pro224Thr)

HGVS:

NC_000010.11:g.62813968G>T
NG_008936.2:g.110933C>A
NM_000399.5:c.670C>AMANE SELECT
NM_001136177.3:c.670C>A
NM_001136178.2:c.670C>A
NM_001136179.3:c.520C>A
NM_001321037.2:c.520C>A
NP_000390.2:p.Pro224Thr
NP_001129649.1:p.Pro224Thr
NP_001129650.1:p.Pro224Thr
NP_001129651.1:p.Pro174Thr
NP_001307966.1:p.Pro174Thr
LRG_239t1:c.670C>A
LRG_239:g.110933C>A
NC_000010.10:g.64573728G>T
NM_000399.3:c.670C>A
NM_000399.4:c.670C>A
p.Pro224Thr

Protein change:

P174T

Links:

dbSNP: rs758869303

NCBI 1000 Genomes Browser:

rs758869303

Molecular consequence:

NM_000399.5:c.670C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001136177.3:c.670C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001136178.2:c.670C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001136179.3:c.520C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001321037.2:c.520C>A - 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

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E1 protein, partial [Rubella virus]
E1 protein, partial [Rubella virus]
gi|226815248|gb|ACO82081.1|

Protein
Homo sapiens nuclear receptor subfamily 1 group H member 3 (NR1H3), RefSeqGene o...
Homo sapiens nuclear receptor subfamily 1 group H member 3 (NR1H3), RefSeqGene on chromosome 11
gi|354459375|ref|NG_030392.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000830274	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 26, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 32376792, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000830274

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 26, 2023)

germline

clinical testing

PubMed (2)
[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

Comprehensive genetic sequence and copy number analysis for Charcot-Marie-Tooth disease in a Canadian cohort of 2517 patients.

Volodarsky M, Kerkhof J, Stuart A, Levy M, Brady LI, Tarnopolsky M, Lin H, Ainsworth P, Sadikovic B.

J Med Genet. 2021 Apr;58(4):284-288. doi: 10.1136/jmedgenet-2019-106641. Epub 2020 May 6.

PubMed [citation]

PMID:: 32376792

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000830274.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 224 of the EGR2 protein (p.Pro224Thr). This variant is present in population databases (rs758869303, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of Charcot-Marie-Tooth disease (PMID: 32376792). ClinVar contains an entry for this variant (Variation ID: 578460). 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 not expected to disrupt EGR2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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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