NM_000166.6(GJB1):c.277A>G (p.Met93Val) AND Charcot-Marie-Tooth Neuropathy X

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jun 2, 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:: RCV003581724.2

Allele description [Variation Report for NM_000166.6(GJB1):c.277A>G (p.Met93Val)]

NM_000166.6(GJB1):c.277A>G (p.Met93Val)

Gene:

GJB1:gap junction protein beta 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq13.1

Genomic location:

Preferred name:

NM_000166.6(GJB1):c.277A>G (p.Met93Val)

HGVS:

NC_000023.11:g.71223984A>G
NG_008357.1:g.13773A>G
NM_000166.6:c.277A>GMANE SELECT
NM_001097642.3:c.277A>G
NP_000157.1:p.Met93Val
NP_001091111.1:p.Met93Val
LRG_245t2:c.277A>G
LRG_245:g.13773A>G
LRG_245p2:p.Met93Val
NC_000023.10:g.70443834A>G
NM_000166.5:c.277A>G

Protein change:

M93V

Links:

dbSNP: rs1602349066

NCBI 1000 Genomes Browser:

rs1602349066

Molecular consequence:

NM_000166.6:c.277A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001097642.3:c.277A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Charcot-Marie-Tooth Neuropathy X
Identifiers:: MedGen: CN118851

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004299613	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 2, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 19259128, 25086786, 12111842, 28334782, 10737979, 27804109, 29998508, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004299613

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 2, 2023)

germline

clinical testing

PubMed (8)
[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

Identification and in silico analysis of 14 novel GJB1, MPZ and PMP22 gene mutations.

Miltenberger-Miltenyi G, Schwarzbraun T, Löscher WN, Wanschitz J, Windpassinger C, Duba HC, Seidl R, Albrecht G, Weirich-Schwaiger H, Zoller H, Utermann G, Auer-Grumbach M, Janecke AR.

Eur J Hum Genet. 2009 Sep;17(9):1154-9. doi: 10.1038/ejhg.2009.29. Epub 2009 Mar 4.

PubMed [citation]

PMID:: 19259128
PMCID:: PMC2986587

Transient, recurrent, white matter lesions in x-linked Charcot-Marie-tooth disease with novel mutation of gap junction protein beta 1 gene in China: a case report.

Zhao Y, Xie Y, Zhu X, Wang H, Li Y, Li J.

BMC Neurol. 2014 Aug 3;14:156. doi: 10.1186/s12883-014-0156-5.

PubMed [citation]

PMID:: 25086786
PMCID:: PMC4131157

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004299613.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Met93 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been observed in individuals with GJB1-related conditions (PMID: 19259128, 25086786), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects GJB1 function (PMID: 12111842, 28334782). 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 GJB1 protein function. ClinVar contains an entry for this variant (Variation ID: 637638). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 10737979, 27804109, 29998508). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 93 of the GJB1 protein (p.Met93Val).

#	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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