ClinVar Genomic variation as it relates to human health
NM_000166.6(GJB1):c.-103C>T
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.-103C>T
Variation ID: 217166 Accession: VCV000217166.37
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xq13.1 X: 71223249 (GRCh38) [ NCBI UCSC ] X: 70443099 (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 Oct 8, 2024 Mar 15, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000166.6:c.-103C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
5 prime UTR NM_001097642.3:c.-16-443C>T intron variant NC_000023.11:g.71223249C>T NC_000023.10:g.70443099C>T NG_008357.1:g.13038C>T LRG_245:g.13038C>T LRG_245t2:c.-103C>T - Protein change
- Other names
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- Canonical SPDI
- NC_000023.11:71223248: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
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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 |
793 | 924 |
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/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Mar 15, 2024 | RCV000201088.15 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 19, 2023 | RCV000228634.12 | |
Pathogenic (1) |
no assertion criteria provided
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Sep 16, 2020 | RCV001276387.2 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Oct 30, 2023 | RCV001570001.23 |
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
(Oct 06, 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
Accession: SCV000255686.3
First in ClinVar: Oct 19, 2015 Last updated: Dec 31, 2022 |
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 clinical features associated … (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 clinical features associated with this gene. In some published literature, this variant is referred to as c.-458C>T or c.-459C>T. This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant significantly affects translation by disrupting an Internal Ribosome Entry Site (IRES) (PMID: 10931843, 23827825, 34089394). (less)
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Pathogenic
(Mar 01, 2022)
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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: SCV002498150.17
First in ClinVar: Apr 08, 2022 Last updated: Oct 08, 2024 |
Comment:
GJB1: PP1:Strong, PM2, PS4:Moderate, PP4, PS3:Supporting
Number of individuals with the variant: 1
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Likely pathogenic
(Oct 14, 2022)
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criteria provided, single submitter
Method: research
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Charcot-Marie-Tooth disease X-linked dominant 1
(X-linked dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Pangenia Genomics, Pangenia Inc.
Accession: SCV003919163.1
First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023 |
Comment:
The GJB1, c.-103C>T variant was detected in multiple affected family members with a clinical diagnosis of CMT. The variant has also been reported in multiple … (more)
The GJB1, c.-103C>T variant was detected in multiple affected family members with a clinical diagnosis of CMT. The variant has also been reported in multiple families of various ethnicities to co-segregate with CMT (PMID: 8757034, 10671058, 19335535, 21918739, 28283593). This variant was reported to affect an IRES (internal ribosomal entry site) and subsequently the translation of GJB1 by luciferase reporter assays in transgenic mice and transfected cells (previously reported as c.-459C>T and c.-458C>T in the literature, PMID: 10931843, 23827825), although a recent study did not recapitulate the results (PMID: 34089394). This variant is found only once in African population in gnomAD genomes, and not found in East Asian population in gnomAD genomes. Furthermore, this variant has been detected in multiple unrelated patients with CMT from various countries (PMID: 18379723, 23827825, 26392352, 28768847, 31211173, 31920494, 33136338, 31827005), and not detected in controls in some studies (PMID: 8757034, 19335535). (less)
Number of individuals with the variant: 2
Sex: male
Ethnicity/Population group: Asian
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Pathogenic
(Dec 19, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000283685.10
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
Comment:
This variant occurs in a non-coding region of the GJB1 gene. It does not change the encoded amino acid sequence of the GJB1 protein. The … (more)
This variant occurs in a non-coding region of the GJB1 gene. It does not change the encoded amino acid sequence of the GJB1 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This variant has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 8757034, 19335535, 23827825, 26392352, 28283593, 28768847). It has also been observed to segregate with disease in related individuals. This variant is also known as c.-458C>T and c.-459C>T. ClinVar contains an entry for this variant (Variation ID: 217166). Studies have shown that this variant alters GJB1 gene expression (PMID: 10931843, 23827825). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Aug 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease X-linked dominant 1
(X-linked inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV004045950.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Amyotrophy involving the shoulder musculature (present) , Sensorimotor neuropathy (present) , Distal lower limb muscle weakness (present) , Upper limb muscle weakness (present) , Gait … (more)
Amyotrophy involving the shoulder musculature (present) , Sensorimotor neuropathy (present) , Distal lower limb muscle weakness (present) , Upper limb muscle weakness (present) , Gait disturbance (present) (less)
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Pathogenic
(Jun 06, 2023)
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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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Revvity Omics, Revvity
Accession: SCV004236843.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Likely pathogenic
(Jan 05, 2024)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease X-linked dominant 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004812545.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
This sequence change in GJB1 is located in the 5' untranslated promotor (P2) region (PMID: 20301548). Multiple functional studies using rat models and luciferase functional … (more)
This sequence change in GJB1 is located in the 5' untranslated promotor (P2) region (PMID: 20301548). Multiple functional studies using rat models and luciferase functional studies, assessing protein translation at the internal ribsome entry site (IRES) showed conflicting results suggesting the mechanism of disease is still unknown and requires further investigation (PMID: 34089394, 10931843, 23827825). This variant is present in a single individual from the East Asian population in the population database gnomAD v4.0 (1/4994 alleles). This variant has also been reported as c.-459C>T in the literature. This variant has been reported in multiple unrelated individuals with Charcot-Marie-Tooth (CMT) neuropathy and segregates with disease in at least two families (PMID: 19335535, 37284795, 23827825, 26392352, 28283593, 31827005, 31211173, 18379723, 31920494, ClinVar ID: 217166). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM2_Supporting, PP1_Strong, PS4 (less)
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Pathogenic
(Mar 15, 2024)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005040232.2
First in ClinVar: May 07, 2024 Last updated: Jul 07, 2024 |
Comment:
Variant summary: GJB1 c.-103C>T is located in the untranslated mRNA region upstream of the initiation codon. The variant was absent in 21640 control chromosomes (gnomAD). … (more)
Variant summary: GJB1 c.-103C>T is located in the untranslated mRNA region upstream of the initiation codon. The variant was absent in 21640 control chromosomes (gnomAD). c.-103C>T has been reported in the literature in multiple individuals affected with Charcot-Marie-Tooth disease X-linked dominant 1 (Record_2023). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 37284795). ClinVar contains an entry for this variant (Variation ID: 217166). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Oct 30, 2023)
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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: SCV001794187.2
First in ClinVar: Aug 21, 2021 Last updated: Nov 25, 2023 |
Comment:
Published functional studies indicate impaired protein expression (PMID: 10931843, 23827825); No data available from ethnically-matched control populations to assess the frequency of this variant; Also … (more)
Published functional studies indicate impaired protein expression (PMID: 10931843, 23827825); No data available from ethnically-matched control populations to assess the frequency of this variant; Also known as c.-459 C>T; This variant is associated with the following publications: (PMID: 31211173, 28283593, 23827825, 8757034, 31827005, 33136338, 34089394, 19335535, 26392352, 10931843) (less)
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Pathogenic
(Feb 28, 2019)
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no assertion criteria provided
Method: provider interpretation
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X-linked hereditary motor and sensory neuropathy
Affected status: yes
Allele origin:
germline
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Codex Genetics Limited
Accession: SCV000995998.1
First in ClinVar: Jan 06, 2020 Last updated: Jan 06, 2020 |
Age: 10-41 years
Sex: mixed
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Charcot-Marie-Tooth disease
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001462640.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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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GJB1 Disorders: Charcot-Marie-Tooth Neuropathy (CMT1X) and Central Nervous System Phenotypes. | Adam MP | - | 2024 | PMID: 20301548 |
Genetic analysis and natural history of Charcot-Marie-Tooth disease CMTX1 due to GJB1 variants. | Record CJ | Brain : a journal of neurology | 2023 | PMID: 37284795 |
Revisiting the pathogenic mechanism of the GJB1 5' UTR c.-103C > T mutation causing CMTX1. | Grosz BR | Neurogenetics | 2021 | PMID: 34089394 |
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 |
Targeted next-generation sequencing panels in the diagnosis of Charcot-Marie-Tooth disease. | Cortese A | Neurology | 2020 | PMID: 31827005 |
A Targeted Gene Panel That Covers Coding, Non-coding and Short Tandem Repeat Regions Improves the Diagnosis of Patients With Neurodegenerative Diseases. | Yu AC | Frontiers in neuroscience | 2019 | PMID: 31920494 |
Mutation spectrum of Charcot-Marie-Tooth disease among the Han Chinese in Taiwan. | Hsu YH | Annals of clinical and translational neurology | 2019 | PMID: 31211173 |
Cross-sectional analysis of a large cohort with X-linked Charcot-Marie-Tooth disease (CMTX1). | Panosyan FB | Neurology | 2017 | PMID: 28768847 |
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. | Nykamp K | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 28492532 |
Mutations in noncoding regions of GJB1 are a major cause of X-linked CMT. | Tomaselli PJ | Neurology | 2017 | PMID: 28283593 |
Application of targeted multi-gene panel testing for the diagnosis of inherited peripheral neuropathy provides a high diagnostic yield with unexpected phenotype-genotype variability. | Antoniadi T | BMC medical genetics | 2015 | PMID: 26392352 |
Mutational analysis of the 5' non-coding region of GJB1 in a Taiwanese cohort with Charcot-Marie-Tooth neuropathy. | Tsai PC | Journal of the neurological sciences | 2013 | PMID: 23827825 |
Two pathogenic mutations located within the 5'-regulatory sequence of the GJB1 gene affecting initiation of transcription and translation. | Kabzińska D | Acta biochimica Polonica | 2011 | PMID: 21918739 |
-459C>T point mutation in 5' non-coding region of human GJB1 gene is linked to X-linked Charcot-Marie-Tooth neuropathy. | Li M | Journal of the peripheral nervous system : JPNS | 2009 | PMID: 19335535 |
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 |
Analysis of a Charcot-Marie-Tooth disease mutation reveals an essential internal ribosome entry site element in the connexin-32 gene. | Hudder A | The Journal of biological chemistry | 2000 | PMID: 10931843 |
Mutation in the nerve-specific 5'non-coding region of Cx32 gene and absence of specific mRNA in a CMTX1 Italian family. Mutations in brief no. 195. Online. | Flagiello L | Human mutation | 1998 | PMID: 10671058 |
Mutations of the noncoding region of the connexin32 gene in X-linked dominant Charcot-Marie-Tooth neuropathy. | Ionasescu VV | Neurology | 1996 | PMID: 8757034 |
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Text-mined citations for rs863224971 ...
HelpRecord last updated Oct 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.