NM_000166.6(GJB1):c.283G>A (p.Val95Met) AND Charcot-Marie-Tooth disease X-linked dominant 1

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Dec 6, 2021
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000011186.18

Allele description [Variation Report for NM_000166.6(GJB1):c.283G>A (p.Val95Met)]

NM_000166.6(GJB1):c.283G>A (p.Val95Met)

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.283G>A (p.Val95Met)

HGVS:

NC_000023.11:g.71223990G>A
NG_008357.1:g.13779G>A
NM_000166.6:c.283G>AMANE SELECT
NM_001097642.3:c.283G>A
NP_000157.1:p.Val95Met
NP_001091111.1:p.Val95Met
LRG_245t2:c.283G>A
LRG_245:g.13779G>A
LRG_245p2:p.Val95Met
NC_000023.10:g.70443840G>A
NM_000166.5:c.283G>A
P08034:p.Val95Met

Protein change:

V95M; VAL95MET

Links:

UniProtKB: P08034#VAR_002072; OMIM: 304040.0011; dbSNP: rs104894821

NCBI 1000 Genomes Browser:

rs104894821

Molecular consequence:

NM_000166.6:c.283G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001097642.3:c.283G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Charcot-Marie-Tooth disease X-linked dominant 1
Synonyms:: CHARCOT-MARIE-TOOTH NEUROPATHY, X-LINKED, 1; CMTX 1; Charcot-Marie-Tooth peroneal muscular atrophy, X-linked; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010549; MedGen: C0393808; Orphanet: 101075; OMIM: 302800

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000031413	OMIM	no assertion criteria provided	Pathogenic (Feb 1, 2012)	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 7477983, 21254193, 21291455
SCV001474497	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Pathogenic (Sep 13, 2019)	germline	clinical testing	Citation Link,
SCV002018426	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 22, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002061774	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 6, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

New connexin32 mutations associated with X-linked Charcot-Marie-Tooth disease.

Bone LJ, Dahl N, Lensch MW, Chance PF, Kelly T, Le Guern E, Magi S, Parry G, Shapiro H, Wang S, et al.

Neurology. 1995 Oct;45(10):1863-6.

PubMed [citation]

PMID:: 7477983

Exome sequencing allows for rapid gene identification in a Charcot-Marie-Tooth family.

Montenegro G, Powell E, Huang J, Speziani F, Edwards YJ, Beecham G, Hulme W, Siskind C, Vance J, Shy M, Züchner S.

Ann Neurol. 2011 Mar;69(3):464-70. doi: 10.1002/ana.22235. Epub 2011 Jan 20.

PubMed [citation]

PMID:: 21254193
PMCID:: PMC3066289

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000031413.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (3)

Description

In a family with X-linked Charcot-Marie-Tooth disease (302800), Bone et al. (1995) found a G-to-A transition in codon 95 of the CX32 gene, resulting in the substitution of methionine for valine (V95M).

Montenegro et al. (2011) reported the use of exome sequencing to identify the V95M mutation in affected members of a large family with Charcot-Marie-Tooth disease and a questionable inheritance pattern. Affected individuals had classic features of the disease, with onset between ages 14 and 40 years of distal sensory impairment and muscle weakness and atrophy affecting the upper and lower limbs. Nerve conduction velocities were in the intermediate range.

In a Korean family with CMTX1, Kim et al. (2012) identified a c.283G-A transition in the GJB1 gene, resulting in a V95M substitution at a highly conserved residue in the TM2 domain. The patients had a demyelinating neuropathy.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001474497.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The GJB1 c.283G>A; p.Val95Met variant (rs104894821) is reported in the literature in multiple individuals affected with X-linked Charcot-Marie-Tooth disease (Bone 1995, Kim 2017, Nam 2016, Montenegro 2011). This variant is reported in ClinVar (Variation ID: 10441), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The valine at codon 95 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional analyses of the variant protein show a significant defect in channel formation and function (Ressot 1998, Wang 2004). Based on available information, this variant is considered to be pathogenic. References: Bone LJ et al. New connexin32 mutations associated with X-linked Charcot-Marie-Tooth disease. Neurology. 1995 Oct;45(10):1863-6. Kim JK et al. X-linked Charcot-Marie-Tooth disease with GJB1 mutation presenting as acute disseminated encephalomyelitis-like illness: A case report. Medicine (Baltimore). 2017 Dec;96(49):e9176. Montenegro G et al. Exome sequencing allows for rapid gene identification in a Charcot-Marie-Tooth family. Ann Neurol. 2011 Mar;69(3):464-70. Nam SH et al. Identification of Genetic Causes of Inherited Peripheral Neuropathies by Targeted Gene Panel Sequencing. Mol Cells. 2016 May 31;39(5):382-8. Ressot C et al. Connexin32 mutations associated with X-linked Charcot-Marie-Tooth disease show two distinct behaviors: loss of function and altered gating properties. J Neurosci. 1998 Jun 1;18(11):4063-75. Wang HL et al. Functional analysis of connexin-32 mutants associated with X-linked dominant Charcot-Marie-Tooth disease. Neurobiol Dis. 2004 Mar;15(2):361-70.

#	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

From Revvity Omics, Revvity, SCV002018426.3

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

#	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

From Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center, SCV002061774.2

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

Description

PS3, PS4, PM2, PP3

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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