NM_000166.6(GJB1):c.223C>T (p.Arg75Trp) AND Charcot-Marie-Tooth Neuropathy X

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 6, 2024
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:: RCV000654844.9

Allele description [Variation Report for NM_000166.6(GJB1):c.223C>T (p.Arg75Trp)]

NM_000166.6(GJB1):c.223C>T (p.Arg75Trp)

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.223C>T (p.Arg75Trp)

HGVS:

NC_000023.11:g.71223930C>T
NG_008357.1:g.13719C>T
NM_000166.6:c.223C>TMANE SELECT
NM_001097642.3:c.223C>T
NP_000157.1:p.Arg75Trp
NP_001091111.1:p.Arg75Trp
NP_001091111.1:p.Arg75Trp
LRG_245t1:c.223C>T
LRG_245t2:c.223C>T
LRG_245:g.13719C>T
LRG_245p1:p.Arg75Trp
LRG_245p2:p.Arg75Trp
NC_000023.10:g.70443780C>T
NM_000166.5:c.223C>T
NM_001097642.2:c.223C>T
P08034:p.Arg75Trp

Protein change:

R75W

Links:

UniProtKB: P08034#VAR_002053; dbSNP: rs116840819

NCBI 1000 Genomes Browser:

rs116840819

Molecular consequence:

NM_000166.6:c.223C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001097642.3:c.223C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Chain B, p51 RT
gi|2512653876|pdb|8DX3|B

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000776746	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 6, 2024)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 9272161, 10732813, 12402337, 14663027, 15719046, 17100997, 12460545, 19369543, 23209285, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000776746

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 6, 2024)

germline

clinical testing

PubMed (10)
[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

Screening for connexin 32 mutations in Charcot-Marie-Tooth disease families with possible X-linked inheritance.

Silander K, Meretoja P, Pihko H, Juvonen V, Issakainen J, Aula P, Savontaus ML.

Hum Genet. 1997 Sep;100(3-4):391-7.

PubMed [citation]

PMID:: 9272161

Mutations in the X-linked form of Charcot-Marie-Tooth disease in the French population.

Latour P, Lévy N, Paret M, Chapon F, Chazot G, Clavelou P, Couratier P, Dumas R, Ollagnon E, Pouget J, Setiey A, Vallat JM, Boucherat M, Fontes M, Vandenberghe A.

Neurogenetics. 1997 Sep;1(2):117-23.

PubMed [citation]

PMID:: 10732813

See all PubMed Citations (10)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000776746.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 75 of the GJB1 protein (p.Arg75Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (CMT) (PMID: 9272161, 10732813, 12402337, 14663027, 15719046, 17100997). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 21082). 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: 12460545, 19369543, 23209285). 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: Sep 29, 2024

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