VCV000246098.15 - ClinVar

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

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic
Pathogenic (4); Likely pathogenic (1)

5 out of 6 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 246098 Accession: VCV000246098.15

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq13.1 X: 71224350 (GRCh38) [ NCBI UCSC ] X: 70444200 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jul 25, 2016	Feb 15, 2026	Jan 6, 2026

HGVS

Nucleotide	Protein	Molecular consequence
NM_000166.6:c.643C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000157.1:p.Arg215Trp	missense
NM_001097642.3:c.643C>T	NP_001091111.1:p.Arg215Trp	missense
NC_000023.11:g.71224350C>T
NC_000023.10:g.70444200C>T
NG_008357.1:g.14139C>T
LRG_245:g.14139C>T
LRG_245t2:c.643C>T	LRG_245p2:p.Arg215Trp
	P08034:p.Arg215Trp

... more HGVS ... less HGVS

Protein change

R215W

Other names

Canonical SPDI

NC_000023.11:71224349:C:T

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA10584644 UniProtKB: P08034#VAR_002129 dbSNP: rs879254099 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
GJB1		-	-	GRCh38 GRCh37	870	1006

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Mar 26, 2024	RCV000236009.4
Charcot-Marie-Tooth disease X-linked dominant 1	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Nov 27, 2023	RCV003388834.3
Charcot-Marie-Tooth Neuropathy X	Pathogenic (1)	criteria provided, single submitter	Jan 6, 2026	RCV000688999.10
Charcot-Marie-Tooth disease	Uncertain significance (1)	no assertion criteria provided	-	RCV000789850.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Nov 18, 2016) C Contributing to aggregate classification	criteria provided, single submitter (Athena Diagnostics Criteria)	not provided	Athena Diagnostics Accession: SCV000613497.1 First in ClinVar: Jul 25, 2016 Last updated: Jul 25, 2016	Publications: PubMed (14) PubMed: 10234007‚ 10732813‚ 11437164‚ 11571214‚ 11835375‚ 16912585‚ 21291455‚ 22464564‚ 25947624‚ 8162049‚ 8698335‚ 8816997‚ 8990008‚ 9187667 Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Nov 27, 2023) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Charcot-Marie-Tooth disease X-linked dominant 1	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004223162.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (3) PubMed: 34326750‚ 8162049‚ 8816997 Comment: show 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. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Mar 26, 2024) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV000293451.11 First in ClinVar: Jul 25, 2016 Last updated: Sep 16, 2024	Comment: show Published functional studies demonstrate a damaging effect as R215W prevents the formation of functional channels (PMID: 8816997, 10234007); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10234007, 11835375, 8162049, 11571214, 32376792, 34326750, 8816997) (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Likely pathogenic (Sep 25, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Charcot-Marie-Tooth disease X-linked dominant 1 (X-linked dominant inheritance)	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV004100753.2 First in ClinVar: Nov 04, 2023 Last updated: Apr 13, 2025	Comment: show Criteria applied: PS4_MOD,PM5,PS3_SUP,PM2_SUP,PP3 (less) Observation: 1 Collection method: clinical testing Allele origin: paternal Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: paternal Affected status: yes Clinical Features: Bilateral tonic-clonic seizure (present) , Focal seizure with eyelid myoclonia (present) , Peripheral neuropathy (present) , Myoclonic seizure (present) , Atypical absence seizure (present) Sex: female

Pathogenic (Jan 06, 2026) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Charcot-Marie-Tooth Neuropathy X	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000816633.9 First in ClinVar: Oct 10, 2018 Last updated: Feb 15, 2026	Publications: PubMed (13) PubMed: 10234007‚ 11437164‚ 11571214‚ 11835375‚ 16912585‚ 22464564‚ 25947624‚ 27098783‚ 28492532‚ 8162049‚ 8698335‚ 8816997‚ 9187667 Comment: show This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 215 of the GJB1 protein (p.Arg215Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Charcot-Marie-Tooth disease, type 1X (CMT1X) (PMID: 8162049, 8698335, 9187667, 11437164, 11571214, 11835375, 16912585, 22464564, 25947624, 27098783). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 246098). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GJB1 protein function. Experimental studies have shown that this missense change affects GJB1 function (PMID: 8816997, 10234007). For these reasons, this variant has been classified as Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (-) N Not contributing to aggregate classification	no assertion criteria provided	Charcot-Marie-Tooth disease	Inherited Neuropathy Consortium Accession: SCV000929235.1 First in ClinVar: Jul 27, 2019 Last updated: Jul 27, 2019	Publications: PubMed (1) PubMed: 16912585 Observation: 1 Collection method: literature only Allele origin: germline Affected status: yes Observation 1 Collection method: literature only Allele origin: germline Affected status: yes

Comment:

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.

Comment:

Published functional studies demonstrate a damaging effect as R215W prevents the formation of functional channels (PMID: 8816997, 10234007); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10234007, 11835375, 8162049, 11571214, 32376792, 34326750, 8816997)

Comment:

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 215 of the GJB1 protein (p.Arg215Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Charcot-Marie-Tooth disease, type 1X (CMT1X) (PMID: 8162049, 8698335, 9187667, 11437164, 11571214, 11835375, 16912585, 22464564, 25947624, 27098783). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 246098). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GJB1 protein function. Experimental studies have shown that this missense change affects GJB1 function (PMID: 8816997, 10234007). For these reasons, this variant has been classified as Pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
GJB1 Gene Analysis in Two Extended Families with X-Linked Charcot-Marie-Tooth Disease.	Kovale S	Case reports in neurology	2021	PMID: 34326750
Mutation Analysis of Gap Junction Protein Beta 1 and Genotype-Phenotype Correlation in X-linked Charcot-Marie-Tooth Disease in Chinese Patients.	Sun B	Chinese medical journal	2016	PMID: 27098783
CMTX1 patients' cells present genomic instability corrected by CamKII inhibitors.	Mones S	Orphanet journal of rare diseases	2015	PMID: 25947624
Hand weakness in Charcot-Marie-Tooth disease 1X.	Arthur-Farraj PJ	Neuromuscular disorders : NMD	2012	PMID: 22464564
X-linked dominant Charcot-Marie-Tooth disease with connexin 32 (Cx32) mutations in Koreans.	Kim Y	Clinical genetics	2012	PMID: 21291455
Mutation frequency for Charcot-Marie-Tooth disease type 1 in the Chinese population is similar to that in the global ethnic patients.	Song S	Genetics in medicine : official journal of the American College of Medical Genetics	2006	PMID: 16912585
Charcot-Marie-Tooth disease and related neuropathies: mutation distribution and genotype-phenotype correlation.	Boerkoel CF	Annals of neurology	2002	PMID: 11835375
Clinical, electrophysiological and molecular genetic characteristics of 93 patients with X-linked Charcot-Marie-Tooth disease.	Dubourg O	Brain : a journal of neurology	2001	PMID: 11571214
Mutation analysis in Chariot-Marie Tooth disease type 1: point mutations in the MPZ gene and the GJB1 gene cause comparable phenotypic heterogeneity.	Young P	Journal of neurology	2001	PMID: 11437164
Altered formation of hemichannels and gap junction channels caused by C-terminal connexin-32 mutations.	Castro C	The Journal of neuroscience : the official journal of the Society for Neuroscience	1999	PMID: 10234007
Mutations in the X-linked form of Charcot-Marie-Tooth disease in the French population.	Latour P	Neurogenetics	1997	PMID: 10732813
Mutational analysis of the MPZ, PMP22 and Cx32 genes in patients of Spanish ancestry with Charcot-Marie-Tooth disease and hereditary neuropathy with liability to pressure palsies.	Bort S	Human genetics	1997	PMID: 9187667
Mutation analysis of the connexin 32 (Cx32) gene in Charcot-Marie-Tooth neuropathy type 1: identification of five new mutations.	Nelis E	Human mutation	1997	PMID: 8990008
Connexin 32 mutations from X-linked Charcot-Marie-Tooth disease patients: functional defects and dominant negative effects.	Omori Y	Molecular biology of the cell	1996	PMID: 8816997
X-linked dominant Charcot-Marie-Tooth neuropathy (CMTX): new mutations in the connexin32 gene.	Ressot C	Human genetics	1996	PMID: 8698335
Mutations in the connexin 32 gene in X-linked dominant Charcot-Marie-Tooth disease (CMTX1).	Fairweather N	Human molecular genetics	1994	PMID: 8162049
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Text-mined citations for rs879254099 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Apr 13, 2026