NM_000166.6(GJB1):c.622G>A (p.Glu208Lys) AND Charcot-Marie-Tooth Neuropathy X

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 8, 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:: RCV000805747.8

Allele description [Variation Report for NM_000166.6(GJB1):c.622G>A (p.Glu208Lys)]

NM_000166.6(GJB1):c.622G>A (p.Glu208Lys)

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.622G>A (p.Glu208Lys)

HGVS:

NC_000023.11:g.71224329G>A
NG_008357.1:g.14118G>A
NM_000166.6:c.622G>AMANE SELECT
NM_001097642.3:c.622G>A
NP_000157.1:p.Glu208Lys
NP_001091111.1:p.Glu208Lys
LRG_245t2:c.622G>A
LRG_245:g.14118G>A
LRG_245p2:p.Glu208Lys
NC_000023.10:g.70444179G>A
NM_000166.5:c.622G>A

Protein change:

E208K

Links:

dbSNP: rs1555937270

NCBI 1000 Genomes Browser:

rs1555937270

Molecular consequence:

NM_000166.6:c.622G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001097642.3:c.622G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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PREDICTED: Rattus norvegicus ST6 N-acetylgalactosaminide alpha-2,6-sialyltransfe...
PREDICTED: Rattus norvegicus ST6 N-acetylgalactosaminide alpha-2,6-sialyltransferase 2 (St6galnac2), transcript variant X1, mRNA
gi|2678879552|ref|XM_039086199.2|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000945715	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 8, 2023)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 8162049, 10737979, 17646144, 25429913, 28448691, 9364054, 9592087, 10848620, 15006706, 14960772, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000945715

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 8, 2023)

germline

clinical testing

PubMed (11)
[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 connexin 32 gene in X-linked dominant Charcot-Marie-Tooth disease (CMTX1)

Fairweather N, Bell C, Cochrane S, Chelly J, Wang S, Mostacciuolo ML, Monaco AP, Haites NE.

Hum Mol Genet. 1994 Jan;3(1):29-34. Erratum in: Hum Mol Genet 1994 Jun;3(6):1034.

PubMed [citation]

PMID:: 8162049

Screening for mutations in the peripheral myelin genes PMP22, MPZ and Cx32 (GJB1) in Russian Charcot-Marie-Tooth neuropathy patients.

Mersiyanova IV, Ismailov SM, Polyakov AV, Dadali EL, Fedotov VP, Nelis E, Löfgren A, Timmerman V, van Broeckhoven C, Evgrafov OV.

Hum Mutat. 2000;15(4):340-7. Erratum in: Hum Mutat 2000;16(2):175.

PubMed [citation]

PMID:: 10737979

See all PubMed Citations (11)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000945715.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 208 of the GJB1 protein (p.Glu208Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with X-linked Charcot-Marie-Tooth disease (CMT) (PMID: 8162049, 10737979, 14960772, 17646144, 25429913, 28448691). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 447439). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GJB1 function (PMID: 9364054, 9592087, 10848620, 15006706). This variant disrupts the p.Glu208 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14960772). 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.

#	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: Oct 20, 2024

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