ClinVar Genomic variation as it relates to human health
NM_000399.5(EGR2):c.1142G>A (p.Arg381His)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000399.5(EGR2):c.1142G>A (p.Arg381His)
Variation ID: 41008 Accession: VCV000041008.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q21.3 10: 62813496 (GRCh38) [ NCBI UCSC ] 10: 64573256 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 May 3, 2013 May 12, 2024 Oct 1, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000399.5:c.1142G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000390.2:p.Arg381His missense NM_001136177.3:c.1142G>A NP_001129649.1:p.Arg381His missense NM_001136178.2:c.1142G>A NP_001129650.1:p.Arg381His missense NM_001136179.3:c.992G>A NP_001129651.1:p.Arg331His missense NM_001321037.2:c.992G>A NP_001307966.1:p.Arg331His missense NC_000010.11:g.62813496C>T NC_000010.10:g.64573256C>T NG_008936.2:g.111405G>A LRG_239:g.111405G>A LRG_239t1:c.1142G>A P11161:p.Arg381His - Protein change
- R381H, R331H
- Other names
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- Canonical SPDI
- NC_000010.11:62813495:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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
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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. |
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EGR2 | No evidence available | No evidence available |
GRCh38 GRCh37 |
399 | 423 |
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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (3) |
criteria provided, single submitter
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Dec 1, 2020 | RCV000033901.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 18, 2023 | RCV000701335.5 | |
Uncertain significance (2) |
no assertion criteria provided
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Aug 14, 2019 | RCV000789745.2 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 1, 2023 | RCV002472942.7 |
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
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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
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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
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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. |
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Pathogenic
(Aug 12, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV002771698.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
This variant was not reported in large, multi-ethnic, general populations (http://gnomad.broadinstitute.org). This variant appears to occur de novo in multiple individuals with clinical features associated … (more)
This variant was not reported in large, multi-ethnic, general populations (http://gnomad.broadinstitute.org). This variant appears to occur de novo in multiple individuals with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. Multiple studies have shown that this variant results in the loss of transcriptional regulatory activity required for normal myelination (PMID: 11734543, 12609493). (less)
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Pathogenic
(Oct 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004125463.5
First in ClinVar: Nov 20, 2023 Last updated: May 12, 2024 |
Comment:
EGR2: PM1, PM2, PM5, PM6, PS4:Moderate, PS3:Supporting
Number of individuals with the variant: 1
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Pathogenic
(Dec 01, 2020)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease type 1D
Affected status: yes
Allele origin:
germline
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CMT Laboratory, Bogazici University
Accession: SCV001548306.1
First in ClinVar: Apr 03, 2021 Last updated: Apr 03, 2021 |
Number of individuals with the variant: 1
Family history: yes
Secondary finding: no
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Pathogenic
(Jan 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease, type I
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000830132.5
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 381 of the EGR2 protein (p.Arg381His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 381 of the EGR2 protein (p.Arg381His). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg381 amino acid residue in EGR2. Other variant(s) that disrupt this residue have been observed in individuals with EGR2-related conditions (PMID: 11239949, 20513111), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects EGR2 function (PMID: 12609493). 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 expected to disrupt EGR2 protein function. ClinVar contains an entry for this variant (Variation ID: 41008). This missense change has been observed in individual(s) with Charcot-Marie-Tooth (CMT) (PMID: 10762521, 12471219, 22765307, 25720245). In at least one individual the variant was observed to be de novo. (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: literature only
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Charcot-Marie-Tooth disease
Affected status: yes
Allele origin:
germline
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Inherited Neuropathy Consortium
Accession: SCV000929123.1
First in ClinVar: Jul 29, 2019 Last updated: Jul 29, 2019 |
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Uncertain significance
(Aug 14, 2019)
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no assertion criteria provided
Method: research
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Charcot-Marie-Tooth disease
Affected status: yes
Allele origin:
germline
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Genesis Genome Database
Accession: SCV000999523.1
First in ClinVar: Dec 06, 2019 Last updated: Dec 06, 2019 |
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Uncertain significance
(Jan 06, 2016)
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no assertion criteria provided
Method: literature only
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Charcot-Marie-Tooth disease type 1D
Affected status: yes
Allele origin:
germline
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Inherited Neuropathy Consortium Ii, University Of Miami
Accession: SCV004174370.1
First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023 |
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not provided
(-)
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no classification provided
Method: literature only
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Charcot-Marie-Tooth disease type 1D
Affected status: not provided
Allele origin:
unknown
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GeneReviews
Accession: SCV000057815.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Charcot-Marie-Tooth Neuropathy Type 1 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY. | Adam MP | - | 2015 | PMID: 20301384 |
The modifying effect a PMP22 deletion in a family with Charcot-Marie-Tooth type 1 neuropathy due to an EGR2 mutation. | Reményi V | Ideggyogyaszati szemle | 2014 | PMID: 25720245 |
Mutational analysis of PMP22, EGR2, LITAF and NEFL in Greek Charcot-Marie-Tooth type 1 patients. | Koutsis G | Clinical genetics | 2013 | PMID: 22765307 |
Adult onset Charcot-Marie-Tooth disease type 1D with an Arg381Cys mutation of EGR2. | Briani C | Muscle & nerve | 2010 | PMID: 20513111 |
Different consequences of EGR2 mutants on the transactivation of human Cx32 promoter. | Musso M | Neurobiology of disease | 2003 | PMID: 12609493 |
Frequency of mutations in the early growth response 2 gene associated with peripheral demyelinating neuropathies. | Vandenberghe N | Journal of medical genetics | 2002 | PMID: 12471219 |
Human Connexin 32, a gap junction protein altered in the X-linked form of Charcot-Marie-Tooth disease, is directly regulated by the transcription factor SOX10. | Bondurand N | Human molecular genetics | 2001 | PMID: 11734543 |
A novel missense mutation in the early growth response 2 gene associated with late-onset Charcot--Marie--Tooth disease type 1. | Yoshihara T | Journal of the neurological sciences | 2001 | PMID: 11239949 |
Text-mined citations for rs281865137 ...
HelpRecord last updated May 12, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.