Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31948496, 27228968, 8698335, 21692908, 18379723, 9401007, 21291455, 28768847, 24123415, 8004109)
ClinVar Genomic variation as it relates to human health
NM_000166.6(GJB1):c.64C>T (p.Arg22Ter)
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.
(10)
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
10
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.64C>T (p.Arg22Ter)
Variation ID: 447441 Accession: VCV000447441.42
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq13.1 X: 71223771 (GRCh38) [ NCBI UCSC ] X: 70443621 (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 Dec 19, 2017 Oct 20, 2024 May 22, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000166.6:c.64C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000157.1:p.Arg22Ter nonsense NM_001097642.3:c.64C>T NP_001091111.1:p.Arg22Ter nonsense NC_000023.11:g.71223771C>T NC_000023.10:g.70443621C>T NG_008357.1:g.13560C>T LRG_245:g.13560C>T LRG_245t2:c.64C>T LRG_245p2:p.Arg22Ter - Protein change
- R22*
- Other names
- -
- Canonical SPDI
- NC_000023.11:71223770: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 |
796 | 928 | |
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 (3) |
criteria provided, multiple submitters, no conflicts
|
Sep 1, 2022 | RCV000516443.19 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
May 22, 2024 | RCV000763633.7 | |
| Pathogenic (2) |
criteria provided, single submitter
|
- | RCV000789221.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 18, 2022 | RCV000796941.8 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 1, 2023 | RCV002367716.3 |
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. |
|
|---|---|---|---|---|---|
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Pathogenic
(Mar 22, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV000613498.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
|
|
|
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: SCV000894501.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Charcot-Marie-Tooth disease
Affected status: yes
Allele origin:
germline
|
Molecular Genetics Laboratory, London Health Sciences Centre
Accession: SCV001336648.1
First in ClinVar: Jun 14, 2020 Last updated: Jun 14, 2020 |
|
|
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Pathogenic
(Apr 11, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001823793.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population … (more)
Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31948496, 27228968, 8698335, 21692908, 18379723, 9401007, 21291455, 28768847, 24123415, 8004109) (less)
|
|
|
Pathogenic
(Oct 18, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Charcot-Marie-Tooth Neuropathy X
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000936476.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 447441). This premature translational stop signal has been observed in individual(s) with Charcot-Marie-Tooth disease type X … (more)
ClinVar contains an entry for this variant (Variation ID: 447441). This premature translational stop signal has been observed in individual(s) with Charcot-Marie-Tooth disease type X (CMTX) (PMID: 8004109, 9401007, 11571214, 21692908). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg22*) in the GJB1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 262 amino acid(s) of the GJB1 protein. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Nov 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002659174.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.64C>T (p.R22*) alteration, located in exon 2 (coding exon 1) of the GJB1 gene, consists of a C to T substitution at nucleotide position … (more)
The c.64C>T (p.R22*) alteration, located in exon 2 (coding exon 1) of the GJB1 gene, consists of a C to T substitution at nucleotide position 64. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 22. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been detected in several individuals with Charcot-Marie-Tooth neuropathy X type 1 (CMTX1) (Ionasescu, 1994; Rouger, 1997; Mandich, 2008; Dubourg, 2001). Based on the available evidence, this alteration is classified as pathogenic. (less)
|
|
|
Pathogenic
(May 22, 2024)
|
criteria provided, single submitter
Method: research
|
Charcot-Marie-Tooth disease X-linked dominant 1
(X-linked dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Neurogenomics Lab, Neuroscience Institute, University Of Cape Town
Accession: SCV003930347.2
First in ClinVar: Aug 19, 2023 Last updated: May 26, 2024 |
Comment:
PM2_supporting: This variant is absent from gnomAD v4.0 (adequate coverage >20x confirmed) and an internal database of 1074 control alleles. PM1 met: variant occurs in … (more)
PM2_supporting: This variant is absent from gnomAD v4.0 (adequate coverage >20x confirmed) and an internal database of 1074 control alleles. PM1 met: variant occurs in the N-terminus connexin domain together with other pathogenic variants. PS4 met: variant identified in = 10 unrelated probands with consistent phenotype for disorder. PVS1 met: null variant (nonsense or frameshift variant, predicted to undergo NMD, exon is present in biologically-relevant transcript) in a gene where LOF is a known mechanism of disease. PP1 met: variant segregates with 3 informative meioses in 1 family (PMID: 8698335). Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases/. (less)
Number of individuals with the variant: 1
Zygosity: Single Heterozygote
Sex: female
Geographic origin: South Africa
|
|
|
Pathogenic
(Sep 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002585130.15
First in ClinVar: Oct 22, 2022 Last updated: Oct 20, 2024 |
Comment:
GJB1: PVS1:Strong, PM2, PS4:Moderate, PP1, PP4
Number of individuals with the variant: 1
|
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: literature only
|
Charcot-Marie-Tooth disease
Affected status: yes
Allele origin:
germline
|
Inherited Neuropathy Consortium
Accession: SCV000928573.1
First in ClinVar: Jul 27, 2019 Last updated: Jul 27, 2019 |
|
|
|
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: SCV004174718.1
First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023 |
|
Comment:
Comment:
ClinVar contains an entry for this variant (Variation ID: 447441). This premature translational stop signal has been observed in individual(s) with Charcot-Marie-Tooth disease type X (CMTX) (PMID: 8004109, 9401007, 11571214, 21692908). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg22*) in the GJB1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 262 amino acid(s) of the GJB1 protein. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.64C>T (p.R22*) alteration, located in exon 2 (coding exon 1) of the GJB1 gene, consists of a C to T substitution at nucleotide position 64. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 22. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been detected in several individuals with Charcot-Marie-Tooth neuropathy X type 1 (CMTX1) (Ionasescu, 1994; Rouger, 1997; Mandich, 2008; Dubourg, 2001). Based on the available evidence, this alteration is classified as pathogenic.
Comment:
PM2_supporting: This variant is absent from gnomAD v4.0 (adequate coverage >20x confirmed) and an internal database of 1074 control alleles. PM1 met: variant occurs in the N-terminus connexin domain together with other pathogenic variants. PS4 met: variant identified in = 10 unrelated probands with consistent phenotype for disorder. PVS1 met: null variant (nonsense or frameshift variant, predicted to undergo NMD, exon is present in biologically-relevant transcript) in a gene where LOF is a known mechanism of disease. PP1 met: variant segregates with 3 informative meioses in 1 family (PMID: 8698335). Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases/.
Comment:
GJB1: PVS1:Strong, PM2, PS4:Moderate, PP1, PP4
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:
Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31948496, 27228968, 8698335, 21692908, 18379723, 9401007, 21291455, 28768847, 24123415, 8004109)
Comment:
ClinVar contains an entry for this variant (Variation ID: 447441). This premature translational stop signal has been observed in individual(s) with Charcot-Marie-Tooth disease type X (CMTX) (PMID: 8004109, 9401007, 11571214, 21692908). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg22*) in the GJB1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 262 amino acid(s) of the GJB1 protein. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.64C>T (p.R22*) alteration, located in exon 2 (coding exon 1) of the GJB1 gene, consists of a C to T substitution at nucleotide position 64. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 22. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been detected in several individuals with Charcot-Marie-Tooth neuropathy X type 1 (CMTX1) (Ionasescu, 1994; Rouger, 1997; Mandich, 2008; Dubourg, 2001). Based on the available evidence, this alteration is classified as pathogenic.
Comment:
PM2_supporting: This variant is absent from gnomAD v4.0 (adequate coverage >20x confirmed) and an internal database of 1074 control alleles. PM1 met: variant occurs in the N-terminus connexin domain together with other pathogenic variants. PS4 met: variant identified in = 10 unrelated probands with consistent phenotype for disorder. PVS1 met: null variant (nonsense or frameshift variant, predicted to undergo NMD, exon is present in biologically-relevant transcript) in a gene where LOF is a known mechanism of disease. PP1 met: variant segregates with 3 informative meioses in 1 family (PMID: 8698335). Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases/.
Comment:
GJB1: PVS1:Strong, PM2, PS4:Moderate, PP1, PP4
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| The mutational profile in a South African cohort with inherited neuropathies and spastic paraplegia. | Mahungu AC | Frontiers in neurology | 2023 | PMID: 37712079 |
| Phenotype expression in women with CMT1X. | Siskind CE | Journal of the peripheral nervous system : JPNS | 2011 | PMID: 21692908 |
| Gap junction beta 1 (GJB1) gene mutations in Italian patients with X-linked Charcot-Marie-Tooth disease. | Mandich P | Journal of human genetics | 2008 | PMID: 18379723 |
| 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 |
| 3rd workshop of the European CMT consortium: 54th ENMC International Workshop on genotype/phenotype correlations in Charcot-Marie-Tooth type 1 and hereditary neuropathy with liability to pressure palsies 28-30 November 1997, Naarden, The Netherlands. | - | Neuromuscular disorders : NMD | 1998 | PMID: 10093067 |
| 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 |
| Connexin32 gene mutations in X-linked dominant Charcot-Marie-Tooth disease (CMTX1). | Janssen EA | Human genetics | 1997 | PMID: 9099841 |
| X-linked dominant Charcot-Marie-Tooth neuropathy (CMTX): new mutations in the connexin32 gene. | Ressot C | Human genetics | 1996 | PMID: 8698335 |
| Point mutations of the connexin32 (GJB1) gene in X-linked dominant Charcot-Marie-Tooth neuropathy. | Ionasescu V | Human molecular genetics | 1994 | PMID: 8004109 |
Text-mined citations for rs1555937020 ...
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 Oct 20, 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.