ClinVar Genomic variation as it relates to human health
NM_000166.6(GJB1):c.490C>T (p.Arg164Trp)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000166.6(GJB1):c.490C>T (p.Arg164Trp)
Variation ID: 217170 Accession: VCV000217170.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq13.1 X: 71224197 (GRCh38) [ NCBI UCSC ] X: 70444047 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Oct 19, 2015 Feb 14, 2024 Sep 23, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000166.6:c.490C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000157.1:p.Arg164Trp missense NM_001097642.3:c.490C>T NP_001091111.1:p.Arg164Trp missense NC_000023.11:g.71224197C>T NC_000023.10:g.70444047C>T NG_008357.1:g.13986C>T LRG_245:g.13986C>T LRG_245t2:c.490C>T LRG_245p2:p.Arg164Trp P08034:p.Arg164Trp - Protein change
- R164W
- Other names
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- Canonical SPDI
- NC_000023.11:71224196:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00009
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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
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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. |
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GJB1 | - | - |
GRCh38 GRCh37 |
791 | 922 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
criteria provided, single submitter
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Mar 11, 2022 | RCV000201175.4 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 27, 2023 | RCV000307118.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 23, 2023 | RCV000793229.8 |
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
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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
(Jul 29, 2016)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000329810.6
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Comment:
The R164W pathogenic variant has been published numerous times in association with CMT (Ionasescu et al., 1995; Ionasescu et al., 1996; Oterino et al., 1996; … (more)
The R164W pathogenic variant has been published numerous times in association with CMT (Ionasescu et al., 1995; Ionasescu et al., 1996; Oterino et al., 1996; Young et al., 2001). Functional studies using dual whole-cell voltage-clamp recordings show that R164W impaired the formation and function of junctional channels (Wang et al., 2004). Additionally, different amino acid substitutions at this same position (R164G/Q) and in nearby residues have been reported in the Human Gene Mutation Database in association with CMT (Stenson et al., 2014), supporting the functional significance of this region of the protein. R164W was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. R164W is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. Therefore, R164W is interpreted to be a pathogenic variant. (less)
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Pathogenic
(Mar 11, 2022)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease X-linked dominant 1
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002581596.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PP1_STR, PS3_MOD, PS4_MOD, PM5, PM2_SUP, PP3
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Number of individuals with the variant: 1
Sex: male
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Pathogenic
(Jun 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV000255690.3
First in ClinVar: Oct 19, 2015 Last updated: Jan 26, 2024 |
Comment:
The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been … (more)
The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been identified in multiple individuals with clinical features associated with this gene and appears to be associated with disease in at least one family. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 15006706) The variant is located in a region that is considered important for protein function and/or structure. (less)
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Pathogenic
(Sep 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth Neuropathy X
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000932572.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD … (more)
The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 164 of the GJB1 protein (p.Arg164Trp). Experimental studies have shown that this missense change affects GJB1 function (PMID: 11571214, 15006706). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg164 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9187667, 25025039, 27844031). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GJB1 protein function. ClinVar contains an entry for this variant (Variation ID: 217170). This variant is also known as c.552C>T. This missense change has been observed in individuals with Charcot-Marie-Tooth disease (CMT) (PMID: 7580242, 8733054, 11437164, 28469099). It has also been observed to segregate with disease in related individuals. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Cross-Sectional Study in a Large Cohort of Chinese Patients With GJB1 Gene Mutations. | Liu X | Frontiers in neurology | 2020 | PMID: 32903794 |
Targeted next-generation sequencing panels in the diagnosis of Charcot-Marie-Tooth disease. | Cortese A | Neurology | 2020 | PMID: 31827005 |
Genetic spectrum and clinical profiles in a southeast Chinese cohort of Charcot-Marie-Tooth disease. | Chen CX | Clinical genetics | 2019 | PMID: 31372974 |
Clinical and Genetic Features of Chinese X-linked Charcot-Marie-Tooth Type 1 Disease. | Lu YY | Chinese medical journal | 2017 | PMID: 28469099 |
Loss of Coupling Distinguishes GJB1 Mutations Associated with CNS Manifestations of CMT1X from Those Without CNS Manifestations. | Abrams CK | Scientific reports | 2017 | PMID: 28071741 |
Clinical and genetic spectra of Charcot-Marie-Tooth disease in Chinese Han patients. | Sun B | Journal of the peripheral nervous system : JPNS | 2017 | PMID: 27862672 |
Phenotypes and cellular effects of GJB1 mutations causing CMT1X in a cohort of 226 Chinese CMT families. | Liu L | Clinical genetics | 2017 | PMID: 27804109 |
Clinical and biophysical characterization of 19 GJB1 mutations. | Tsai PC | Annals of clinical and translational neurology | 2016 | PMID: 27844031 |
Three novel mutations and genetic epidemiology analysis of the Gap Junction Beta 1 (GJB1) gene among Hungarian Charcot-Marie-Tooth disease patients. | Milley GM | Neuromuscular disorders : NMD | 2016 | PMID: 27544631 |
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 |
Improving molecular diagnosis of Chinese patients with Charcot-Marie-Tooth by targeted next-generation sequencing and functional analysis. | Li LX | Oncotarget | 2016 | PMID: 27027447 |
Identification of Genetic Causes of Inherited Peripheral Neuropathies by Targeted Gene Panel Sequencing. | Nam SH | Molecules and cells | 2016 | PMID: 27025386 |
X-Linked Hereditary Motor Sensory Neuropathy Type 1 (CMTX1) in a Three-Generation Gelao Chinese Family. | Shu XM | Neuropediatrics | 2015 | PMID: 26479765 |
Charcot-Marie-Tooth disease: frequency of genetic subtypes in a Southern Italy population. | Manganelli F | Journal of the peripheral nervous system : JPNS | 2014 | PMID: 25429913 |
Genetic diagnosis of Charcot-Marie-Tooth disease in a population by next-generation sequencing. | Høyer H | BioMed research international | 2014 | PMID: 25025039 |
Segregation analysis in families with Charcot-Marie-Tooth disease allows reclassification of putative disease causing mutations. | Østern R | BMC medical genetics | 2014 | PMID: 24444136 |
X-linked Charcot-Marie-Tooth disease and progressive-relapsing central demyelinating disease. | Isoardo G | Neurology | 2005 | PMID: 16301507 |
Functional analysis of connexin-32 mutants associated with X-linked dominant Charcot-Marie-Tooth disease. | Wang HL | Neurobiology of disease | 2004 | PMID: 15006706 |
Transient cerebral white matter lesions in a patient with connexin 32 missense mutation. | Schelhaas HJ | Neurology | 2002 | PMID: 12499506 |
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 |
Charcot-Marie-Tooth disease type I and related demyelinating neuropathies: Mutation analysis in a large cohort of Italian families. | Mostacciuolo ML | Human mutation | 2001 | PMID: 11438991 |
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 |
X-linked Charcot-Marie-Tooth disease and connexin32. | Ionasescu VV | Cell biology international | 1998 | PMID: 10873293 |
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 |
Mutations of the noncoding region of the connexin32 gene in X-linked dominant Charcot-Marie-Tooth neuropathy. | Ionasescu VV | Neurology | 1996 | PMID: 8757034 |
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 |
Arginine-164-tryptophan substitution in connexin32 associated with X linked dominant Charcot-Marie-Tooth disease. | Oterino A | Journal of medical genetics | 1996 | PMID: 8733054 |
New point mutations and deletions of the connexin 32 gene in X-linked Charcot-Marie-Tooth neuropathy. | Ionasescu V | Neuromuscular disorders : NMD | 1995 | PMID: 7580242 |
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Text-mined citations for rs139643362 ...
HelpRecord last updated May 08, 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.