ClinVar Genomic variation as it relates to human health
NM_000166.6(GJB1):c.548G>A (p.Arg183His)
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.548G>A (p.Arg183His)
Variation ID: 447435 Accession: VCV000447435.32
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq13.1 X: 71224255 (GRCh38) [ NCBI UCSC ] X: 70444105 (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 Dec 19, 2017 Apr 15, 2024 Jan 13, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000166.6:c.548G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000157.1:p.Arg183His missense NM_001097642.3:c.548G>A NP_001091111.1:p.Arg183His missense NC_000023.11:g.71224255G>A NC_000023.10:g.70444105G>A NG_008357.1:g.14044G>A LRG_245:g.14044G>A LRG_245t2:c.548G>A LRG_245p2:p.Arg183His - Protein change
- R183H
- Other names
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- Canonical SPDI
- NC_000023.11:71224254:G:A
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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
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The frequency of the allele represented by this VCV record.
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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
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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 |
788 | 917 |
Conditions - Germline
Condition
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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 (2) |
criteria provided, multiple submitters, no conflicts
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Mar 10, 2021 | RCV000517827.18 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 13, 2024 | RCV000654852.11 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV000789837.2 | |
Pathogenic (1) |
criteria provided, single submitter
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May 4, 2022 | RCV002248750.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 3, 2022 | RCV002350137.2 |
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
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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
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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
(Mar 10, 2021)
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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 Inc
Accession: SCV000613491.2
First in ClinVar: Dec 19, 2017 Last updated: Sep 19, 2021 |
Comment:
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with X-linked Charcot-Marie-Tooth neuropathy, … (more)
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with X-linked Charcot-Marie-Tooth neuropathy, type 1 (CMTX1). At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant causes aberrant cellular localization of this gap junction protein (PMID: 12111842). This variant alters a critical location within the protein, and is expected to severely affect function and cause disease. Computational tools predict that this variant is damaging. (less)
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Pathogenic
(May 04, 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: unknown
Allele origin:
germline
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Mendelics
Accession: SCV002516474.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
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Pathogenic
(Jan 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002650057.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.R183H pathogenic mutation (also known as c.548G>A), located in coding exon 1 of the GJB1 gene, results from a G to A substitution at … (more)
The p.R183H pathogenic mutation (also known as c.548G>A), located in coding exon 1 of the GJB1 gene, results from a G to A substitution at nucleotide position 548. The arginine at codon 183 is replaced by histidine, an amino acid with highly similar properties. This alteration has been detected in multiple individuals with Charcot-Marie-Tooth neuropathy X type 1 (CMTX1) in several different families of various origin (Bort S et al. Hum Genet, 1997 Jun;99:746-54; Mersiyanova IV et al. Hum Mutat, 2000;15:340-7; Hattori N et al. Brain, 2003 Jan;126:134-51; Chen CX et al. Ann Clin Transl Neurol, 2020 12;7:2381-2392; Kochaski A et al. J Appl Genet, 2004;45:95-100; Niu J et al. Front Neurol, 2019 Jan;10:1406; Chen B et al. Clin Neurol Neurosurg, 2019 Sep;184:105430; Lu YY et al. Chin Med J (Engl), 2017 May;130:1049-1054; Zhang RX et al. Beijing Da Xue Xue Bao Yi Xue Ban, 2005 Feb;37:68-71; Hong YB et al. J Peripher Nerv Syst, 2017 09;22:172-181; Casasnovas C et al. Clin Genet, 2006 Dec;70:516-23; Micheau P et al. Ann Chir Plast, 1975;20:311-8). Experimental studies show this alteration led to abnormal protein function (Kleopa KA et al. J Neurosci Res, 2002 Jun;68:522-34). (Tsai PC et al. Ann Clin Transl Neurol, 2016 11;3:854-865). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jan 13, 2024)
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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: SCV000776754.8
First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 183 of the GJB1 protein (p.Arg183His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 183 of the GJB1 protein (p.Arg183His). 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 X (PMID: 9187667, 14960772, 15719046, 27027447, 27844031, 28469099). ClinVar contains an entry for this variant (Variation ID: 447435). 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 with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GJB1 function (PMID: 12111842, 27844031). This variant disrupts the p.Arg183 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9187667, 11271367, 12111842). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001245766.20
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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Uncertain significance
(-)
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no assertion criteria provided
Method: literature only
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Charcot-Marie-Tooth disease
Affected status: yes
Allele origin:
germline
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Inherited Neuropathy Consortium
Accession: SCV000929221.1
First in ClinVar: Jul 27, 2019 Last updated: Jul 27, 2019 |
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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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Identification and functional characterization of novel GDAP1 variants in Chinese patients with Charcot-Marie-Tooth disease. | Chen CX | Annals of clinical and translational neurology | 2020 | PMID: 33136338 |
GJB1 Mutation-A Disease Spectrum: Report of Case Series. | Niu J | Frontiers in neurology | 2020 | PMID: 32010055 |
Three novel mutations in a group of Chinese patients with X-linked Charcot-Marie-Tooth disease. | Chen B | Clinical neurology and neurosurgery | 2019 | PMID: 31323543 |
Clinical and Genetic Features of Chinese X-linked Charcot-Marie-Tooth Type 1 Disease. | Lu YY | Chinese medical journal | 2017 | PMID: 28469099 |
Clinical characterization and genetic analysis of Korean patients with X-linked Charcot-Marie-Tooth disease type 1. | Hong YB | Journal of the peripheral nervous system : JPNS | 2017 | PMID: 28448691 |
Clinical and biophysical characterization of 19 GJB1 mutations. | Tsai PC | Annals of clinical and translational neurology | 2016 | PMID: 27844031 |
Improving molecular diagnosis of Chinese patients with Charcot-Marie-Tooth by targeted next-generation sequencing and functional analysis. | Li LX | Oncotarget | 2016 | PMID: 27027447 |
Clinical and molecular analysis of X-linked Charcot-Marie-Tooth disease type 1 in Spanish population. | Casasnovas C | Clinical genetics | 2006 | PMID: 17100997 |
Mutation screening of Cx32 in Han Chinese patients with Charcot-Marie-Tooth disease. | Zhang RX | Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences | 2005 | PMID: 15719046 |
Molecular genetic analysis of the GJB1 gene: a study of six mutations. | Kochański A | Journal of applied genetics | 2004 | PMID: 14960772 |
Demyelinating and axonal features of Charcot-Marie-Tooth disease with mutations of myelin-related proteins (PMP22, MPZ and Cx32): a clinicopathological study of 205 Japanese patients. | Hattori N | Brain : a journal of neurology | 2003 | PMID: 12477701 |
Cellular mechanisms of connexin32 mutations associated with CNS manifestations. | Kleopa KA | Journal of neuroscience research | 2002 | PMID: 12111842 |
Pathological findings in the x-linked form of Charcot-Marie-Tooth disease: a morphometric and ultrastructural analysis. | Hahn AF | Acta neuropathologica | 2001 | PMID: 11271367 |
Screening for mutations in the peripheral myelin genes PMP22, MPZ and Cx32 (GJB1) in Russian Charcot-Marie-Tooth neuropathy patients. | Mersiyanova IV | Human mutation | 2000 | PMID: 10737979 |
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 |
[Use of the greater omentum: anatomical and radiological basis]. | Micheau P | Annales de chirurgie plastique | 1975 | PMID: 1211842 |
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Text-mined citations for rs1555937233 ...
HelpRecord last updated Apr 15, 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.