Published functional studies demonstrate incomplete channel assembly and significantly reduced currents (Nualart-Marti et al., 2013; Castro et al., 1999); Nonsense variant predicted to result in protein truncation in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 8737658, 7477983, 8958325, 21871435, 11571214, 30042657, 25025039, 9401007, 8076700, 24123415, 27228968, 16442804, 10234007, 23587648, 8816997, 9592087, 8162049, 21291455, 28448691, 27844031, 31211173, 30881289, 9364054, 29077882, 34429228, 37284795)
ClinVar Genomic variation as it relates to human health
NM_000166.6(GJB1):c.658C>T (p.Arg220Ter)
Germline
Classification
Help
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.
(9)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000166.6(GJB1):c.658C>T (p.Arg220Ter)
Variation ID: 10435 Accession: VCV000010435.22
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: Xq13.1 X: 71224365 (GRCh38) [ NCBI UCSC ] X: 70444215 (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 Mar 23, 2014 May 1, 2024 Nov 27, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000166.6:c.658C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000157.1:p.Arg220Ter nonsense NM_001097642.3:c.658C>T NP_001091111.1:p.Arg220Ter nonsense NC_000023.11:g.71224365C>T NC_000023.10:g.70444215C>T NG_008357.1:g.14154C>T LRG_245:g.14154C>T LRG_245t2:c.658C>T LRG_245p2:p.Arg220Ter - Protein change
- R220*
- Other names
- -
- Canonical SPDI
- NC_000023.11:71224364:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe 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
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 | ||
|---|---|---|---|---|---|---|
| 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 |
795 | 927 | |
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. |
|---|---|---|---|---|
| Pathogenic (4) |
criteria provided, single submitter
|
Oct 31, 2018 | RCV000011180.11 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 27, 2023 | RCV000466155.12 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Aug 30, 2023 | RCV000236998.12 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 21, 2020 | RCV002362576.2 |
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. |
More information
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
(Jan 21, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV000613499.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
|
|
|
Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Charcot-Marie-Tooth disease X-linked dominant 1
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000894502.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
|
Pathogenic
(Aug 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000292877.11
First in ClinVar: Jul 25, 2016 Last updated: Sep 07, 2023 |
Comment:
Published functional studies demonstrate incomplete channel assembly and significantly reduced currents (Nualart-Marti et al., 2013; Castro et al., 1999); Nonsense variant predicted to result in … (more)
Published functional studies demonstrate incomplete channel assembly and significantly reduced currents (Nualart-Marti et al., 2013; Castro et al., 1999); Nonsense variant predicted to result in protein truncation in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 8737658, 7477983, 8958325, 21871435, 11571214, 30042657, 25025039, 9401007, 8076700, 24123415, 27228968, 16442804, 10234007, 23587648, 8816997, 9592087, 8162049, 21291455, 28448691, 27844031, 31211173, 30881289, 9364054, 29077882, 34429228, 37284795) (less)
|
|
|
Pathogenic
(Apr 01, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000227040.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Pathogenic
(Nov 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Charcot-Marie-Tooth Neuropathy X
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000544782.10
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg220*) in the GJB1 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Arg220*) in the GJB1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 64 amino acid(s) of the GJB1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with X-linked dominant Charcot-Marie-Tooth disease (PMID: 7477983, 8162049, 9364054, 21291455). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 10435). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on GJB1 function (PMID: 8816997, 9364054, 9592087). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(May 21, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002664676.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.R220* pathogenic mutation (also known as c.658C>T), located in coding exon 1 of the GJB1 gene, results from a C to T substitution at … (more)
The p.R220* pathogenic mutation (also known as c.658C>T), located in coding exon 1 of the GJB1 gene, results from a C to T substitution at nucleotide position 658. This changes the amino acid from an arginine to a stop codon within coding exon 1. This stop codon occurs at the 3' terminus of GJB1 and is not expected to trigger nonsense-mediated mRNA decay; however, it impacts the last 64 amino acids and removes approximately 23% of the protein. This alteration has been detected in multiple patients and families with X-linked dominant Charcot-Marie-Tooth disease and has been shown to co-segregate with disease (Fairweather N et al. Hum. Mol. Genet., 1994 Jan;3:29-34; Ionasescu VV. Cell Biol. Int., 1998 Nov;22:807-13; Tsai PC et al. Ann Clin Transl Neurol, 2016 11;3:854-865). Functional studies have demonstrated protein mislocalization and altered gap junction channel activity (Tsai PC et al. Ann Clin Transl Neurol, 2016 11;3:854-865; Ressot C et al. J. Neurosci., 1998 Jun;18:4063-75; Carrer A et al. Hum. Mol. Genet., 2018 01;27:80-94). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
|
|
|
Pathogenic
(Feb 01, 2012)
|
no assertion criteria provided
Method: literature only
|
CHARCOT-MARIE-TOOTH DISEASE, X-LINKED DOMINANT, 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000031407.2
First in ClinVar: Apr 04, 2013 Last updated: Mar 23, 2014 |
Comment on evidence:
In a family with X-linked Charcot-Marie-Tooth disease (302800), Fairweather et al. (1994) found a C-to-T transition in codon 220 of the CX32 gene, resulting in … (more)
In a family with X-linked Charcot-Marie-Tooth disease (302800), Fairweather et al. (1994) found a C-to-T transition in codon 220 of the CX32 gene, resulting in a stop signal in place of an arginine (R220X). The same mutation was found in an unrelated Virginia family by Bone et al. (1995). In a Korean patient with CMTX1, Kim et al. (2012) identified a c.658C-T transition in the GJB1 gene, resulting in an R220X substitution in the C-terminal domain. The patient had a demyelinating neuropathy. (less)
|
|
|
Uncertain significance
(Jan 06, 2016)
|
no assertion criteria provided
Method: literature only
|
Charcot-Marie-Tooth disease X-linked dominant 1
Affected status: yes
Allele origin:
germline
|
Inherited Neuropathy Consortium Ii, University Of Miami
Accession: SCV004174708.1
First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023 |
|
|
|
not provided
(-)
|
no classification provided
Method: phenotyping only
|
Charcot-Marie-Tooth disease X-linked dominant 1
Affected status: unknown
Allele origin:
unknown
|
GenomeConnect - Invitae Patient Insights Network
Accession: SCV004228667.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
Variant interpreted as Pathogenic and reported on 10-28-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided … (more)
Variant interpreted as Pathogenic and reported on 10-28-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Clinical Features:
Abnormal cardiovascular system morphology (present) , Abnormal inflammatory response (present) , Abnormality of the anus (present) , Abnormal stomach morphology (present) , Abnormal curvature of … (more)
Abnormal cardiovascular system morphology (present) , Abnormal inflammatory response (present) , Abnormality of the anus (present) , Abnormal stomach morphology (present) , Abnormal curvature of the vertebral column (present) (less)
Indication for testing: Diagnostic
Age: 70-79 years
Sex: female
Method: Gene Panel Sequencing
Testing laboratory: Invitae
Date variant was reported to submitter: 2019-10-28
Testing laboratory interpretation: Pathogenic
|
Comment:
Comment:
This sequence change creates a premature translational stop signal (p.Arg220*) in the GJB1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 64 amino acid(s) of the GJB1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with X-linked dominant Charcot-Marie-Tooth disease (PMID: 7477983, 8162049, 9364054, 21291455). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 10435). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on GJB1 function (PMID: 8816997, 9364054, 9592087). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.R220* pathogenic mutation (also known as c.658C>T), located in coding exon 1 of the GJB1 gene, results from a C to T substitution at nucleotide position 658. This changes the amino acid from an arginine to a stop codon within coding exon 1. This stop codon occurs at the 3' terminus of GJB1 and is not expected to trigger nonsense-mediated mRNA decay; however, it impacts the last 64 amino acids and removes approximately 23% of the protein. This alteration has been detected in multiple patients and families with X-linked dominant Charcot-Marie-Tooth disease and has been shown to co-segregate with disease (Fairweather N et al. Hum. Mol. Genet., 1994 Jan;3:29-34; Ionasescu VV. Cell Biol. Int., 1998 Nov;22:807-13; Tsai PC et al. Ann Clin Transl Neurol, 2016 11;3:854-865). Functional studies have demonstrated protein mislocalization and altered gap junction channel activity (Tsai PC et al. Ann Clin Transl Neurol, 2016 11;3:854-865; Ressot C et al. J. Neurosci., 1998 Jun;18:4063-75; Carrer A et al. Hum. Mol. Genet., 2018 01;27:80-94). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
Variant interpreted as Pathogenic and reported on 10-28-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
Published functional studies demonstrate incomplete channel assembly and significantly reduced currents (Nualart-Marti et al., 2013; Castro et al., 1999); Nonsense variant predicted to result in protein truncation in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 8737658, 7477983, 8958325, 21871435, 11571214, 30042657, 25025039, 9401007, 8076700, 24123415, 27228968, 16442804, 10234007, 23587648, 8816997, 9592087, 8162049, 21291455, 28448691, 27844031, 31211173, 30881289, 9364054, 29077882, 34429228, 37284795)
Comment:
This sequence change creates a premature translational stop signal (p.Arg220*) in the GJB1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 64 amino acid(s) of the GJB1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with X-linked dominant Charcot-Marie-Tooth disease (PMID: 7477983, 8162049, 9364054, 21291455). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 10435). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on GJB1 function (PMID: 8816997, 9364054, 9592087). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.R220* pathogenic mutation (also known as c.658C>T), located in coding exon 1 of the GJB1 gene, results from a C to T substitution at nucleotide position 658. This changes the amino acid from an arginine to a stop codon within coding exon 1. This stop codon occurs at the 3' terminus of GJB1 and is not expected to trigger nonsense-mediated mRNA decay; however, it impacts the last 64 amino acids and removes approximately 23% of the protein. This alteration has been detected in multiple patients and families with X-linked dominant Charcot-Marie-Tooth disease and has been shown to co-segregate with disease (Fairweather N et al. Hum. Mol. Genet., 1994 Jan;3:29-34; Ionasescu VV. Cell Biol. Int., 1998 Nov;22:807-13; Tsai PC et al. Ann Clin Transl Neurol, 2016 11;3:854-865). Functional studies have demonstrated protein mislocalization and altered gap junction channel activity (Tsai PC et al. Ann Clin Transl Neurol, 2016 11;3:854-865; Ressot C et al. J. Neurosci., 1998 Jun;18:4063-75; Carrer A et al. Hum. Mol. Genet., 2018 01;27:80-94). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
Variant interpreted as Pathogenic and reported on 10-28-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Cx32 hemichannel opening by cytosolic Ca2+ is inhibited by the R220X mutation that causes Charcot-Marie-Tooth disease. | Carrer A | Human molecular genetics | 2018 | PMID: 29077882 |
| Clinical and biophysical characterization of 19 GJB1 mutations. | Tsai PC | Annals of clinical and translational neurology | 2016 | PMID: 27844031 |
| X-linked dominant Charcot-Marie-Tooth disease with connexin 32 (Cx32) mutations in Koreans. | Kim Y | Clinical genetics | 2012 | PMID: 21291455 |
| X-linked Charcot-Marie-Tooth disease and connexin32. | Ionasescu VV | Cell biology international | 1998 | PMID: 10873293 |
| Connexin32 mutations associated with X-linked Charcot-Marie-Tooth disease show two distinct behaviors: loss of function and altered gating properties. | Ressot C | The Journal of neuroscience : the official journal of the Society for Neuroscience | 1998 | PMID: 9592087 |
| Charcot-Marie-Tooth disease with intermediate motor nerve conduction velocities: characterization of 14 Cx32 mutations in 35 families. | Rouger H | Human mutation | 1997 | PMID: 9401007 |
| Altered trafficking of mutant connexin32. | Deschênes SM | The Journal of neuroscience : the official journal of the Society for Neuroscience | 1997 | PMID: 9364054 |
| 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 |
| Correlation between connexin 32 gene mutations and clinical phenotype in X-linked dominant Charcot-Marie-Tooth neuropathy. | Ionasescu V | American journal of medical genetics | 1996 | PMID: 8737658 |
| New connexin32 mutations associated with X-linked Charcot-Marie-Tooth disease. | Bone LJ | Neurology | 1995 | PMID: 7477983 |
| Mutations in the connexin 32 gene in X-linked dominant Charcot-Marie-Tooth disease (CMTX1). | Fairweather N | Human molecular genetics | 1994 | PMID: 8162049 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GJB1 | - | - | - | - |
| click to load more click to collapse | ||||
Text-mined citations for rs104894814 ...
HelpThese 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 Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.