NM_000166.6(GJB1):c.643C>T (p.Arg215Trp) AND Charcot-Marie-Tooth disease X-linked dominant 1

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Nov 27, 2023
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:: RCV003388834.3

Allele description [Variation Report for NM_000166.6(GJB1):c.643C>T (p.Arg215Trp)]

NM_000166.6(GJB1):c.643C>T (p.Arg215Trp)

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.643C>T (p.Arg215Trp)

HGVS:

NC_000023.11:g.71224350C>T
NG_008357.1:g.14139C>T
NM_000166.6:c.643C>TMANE SELECT
NM_001097642.3:c.643C>T
NP_000157.1:p.Arg215Trp
NP_001091111.1:p.Arg215Trp
LRG_245t2:c.643C>T
LRG_245:g.14139C>T
LRG_245p2:p.Arg215Trp
NC_000023.10:g.70444200C>T
NM_000166.5:c.643C>T
P08034:p.Arg215Trp

Protein change:

R215W

Links:

UniProtKB: P08034#VAR_002129; dbSNP: rs879254099

Molecular consequence:

NM_000166.6:c.643C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001097642.3:c.643C>T - 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; CHARCOT-MARIE-TOOTH PERONEAL MUSCULAR ATROPHY, X-LINKED; HEREDITARY MOTOR AND SENSORY NEUROPATHY, 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
SCV004100753	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 25, 2023)	paternal	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004223162	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Nov 27, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 8162049, 34326750, 8816997 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004100753

Institute of Human Genetics, University of Leipzig Medical Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Sep 25, 2023)

paternal

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004223162

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Nov 27, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	paternal	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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

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

See all PubMed Citations (4)

Details of each submission

From Institute of Human Genetics, University of Leipzig Medical Center, SCV004100753.2

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

Description

Criteria applied: PS4_MOD,PM5,PS3_SUP,PM2_SUP,PP3

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004223162.1

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

Description

Variant summary: GJB1 c.643C>T (p.Arg215Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 179956 control chromosomes. c.643C>T has been reported in the literature in multiple familial individuals affected with Charcot-Marie-Tooth disease X-linked dominant 1 (example, Fairweather_1994, Kovale_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in about 20% of normal GJB1 levels, diminished gap junctional intercellular communication, and interfering WT allele of GJB1 through a dominant-negative mechanism in Hela cells (Omori_1996). The following publications have been ascertained in the context of this evaluation (PMID: 8162049, 34326750, 8816997). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was 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: Apr 12, 2026

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