ClinVar Genomic variation as it relates to human health
NM_004004.6(GJB2):c.134G>A (p.Gly45Glu)
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_004004.6(GJB2):c.134G>A (p.Gly45Glu)
Variation ID: 17033 Accession: VCV000017033.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q12.11 13: 20189448 (GRCh38) [ NCBI UCSC ] 13: 20763587 (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 Mar 29, 2015 Feb 14, 2024 Nov 28, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004004.6:c.134G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003995.2:p.Gly45Glu missense NC_000013.11:g.20189448C>T NC_000013.10:g.20763587C>T NG_008358.1:g.8528G>A LRG_1350:g.8528G>A LRG_1350t1:c.134G>A LRG_1350p1:p.Gly45Glu P29033:p.Gly45Glu - Protein change
- G45E
- Other names
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- Canonical SPDI
- NC_000013.11:20189447: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.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD), exomes 0.00001
- Links
- Comment on variant
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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GJB2 | Dosage sensitivity unlikely | No evidence available |
GRCh38 GRCh37 |
557 | 620 |
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 (2) |
criteria provided, multiple submitters, no conflicts
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Aug 21, 2019 | RCV000022510.34 | |
Pathogenic (1) |
no assertion criteria provided
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Dec 1, 2011 | RCV000018561.31 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 28, 2023 | RCV001851914.5 |
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
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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 25, 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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GeneDx
Accession: SCV002499796.2
First in ClinVar: Apr 23, 2022 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a dominant negative effect on hemichannel function, resulting in increased cell death (Gerido et al., 2007; Mese et al., 2008); Published … (more)
Published functional studies demonstrate a dominant negative effect on hemichannel function, resulting in increased cell death (Gerido et al., 2007; Mese et al., 2008); Published functional studies demonstrate that the dominant negative effect of p.(G45E) on gap junction formation is neutralized by the presence of p.(Y136*) on the same allele (in cis), and that the complex allele results instead in a loss of protein function (Rodriguez-Paris et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24359977, 27087580, 16950989, 21292415, 20584891, 30287322, 12560944, 23756814, 19043807, 26763877, 25388846, 31160754, 10633133, 31331740, 17146396, 17428836, 22031297, 10501520, 15633193, 24785414, 16885744, 18024254, 27761313, 20412116) (less)
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Pathogenic
(Aug 21, 2019)
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criteria provided, single submitter
Method: clinical testing
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Deafness, autosomal recessive 1A
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001360714.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: GJB2 c.134G>A (p.Gly45Glu) results in a non-conservative amino acid change located in the Connexin, N-terminal domain (IPR013092)/first extracellular loop domain of the encoded … (more)
Variant summary: GJB2 c.134G>A (p.Gly45Glu) results in a non-conservative amino acid change located in the Connexin, N-terminal domain (IPR013092)/first extracellular loop domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250912 control chromosomes. c.134G>A has been reported as a de-novo variant or as a somatic mosaic in the literature in multiple individuals affected with Keratitis Ichthyosis Deafness Syndrome (KID) (Janecke_2005, Griffith_2006, Jonard_2008, Sbidian_2010, Ogawa_2014, Eskin-Schwartz_2016). These data indicate that the variant is very likely to be associated with disease. Co-occurrence in cis with another pathogenic variant have been reported in the Japanese population (GJB2 c.408C>A, p.Tyr436*), providing supporting evidence for a benign role in the setting of Autosomal Recessive Non-syndromic deafness (Fuse_1999, Ogawa_2014). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a complete inability to form functional gap junctions (Rodriguez-Paris_2016). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant when observed in isolation was classified as pathogenic for a phenotype of KID. (less)
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Likely pathogenic
(Dec 13, 2014)
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criteria provided, single submitter
Method: literature only
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Deafness, autosomal recessive 1A
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000220956.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
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Pathogenic
(Nov 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002241910.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 45 of the GJB2 protein … (more)
This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 45 of the GJB2 protein (p.Gly45Glu). This variant is present in population databases (rs72561723, gnomAD 0.003%). This variant has been observed in individual(s) with autosomal dominant keratitis-ichthyosis-deafness syndrome, in the absence of p.Tyr136* (PMID: 15633193, 16885744, 18024254, 24785414). In at least one individual the variant was observed to be de novo. Therefore, when present alone (i.e. without a loss of function variant in cis that causes nonsense-mediated decay of the transcript), this variant is expected to be causative for autosomal dominant keratitis-ichthyosis-deafness syndrome. This variant has also been reported in combination with p.Tyr136* in individuals with autosomal recessive non-syndromic deafness (PMID: 10501520, 26763877); the p.[Tyr136*;Gly45Gly] haplotype is expected to be causative for autosomal recessive non-syndromic deafness. ClinVar contains an entry for this variant (Variation ID: 17033). 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 expected to disrupt GJB2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GJB2 function (PMID: 17428836, 22031297, 24785414, 27761313). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 01, 2011)
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no assertion criteria provided
Method: literature only
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KERATITIS-ICHTHYOSIS-DEAFNESS SYNDROME, AUTOSOMAL DOMINANT
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000038843.4
First in ClinVar: Apr 04, 2013 Last updated: Jan 19, 2020 |
Comment on evidence:
In an Austrian girl with the fatal form of KID syndrome (KIDAD; 148210), Janecke et al. (2005) identified a heterozygous 134G-A transition in the GJB2 … (more)
In an Austrian girl with the fatal form of KID syndrome (KIDAD; 148210), Janecke et al. (2005) identified a heterozygous 134G-A transition in the GJB2 gene, resulting in a gly45-to-glu (G45E) substitution. At the age of 2 months, the patient showed a generalized scaled appearance resembling ichthyosiform erythroderma. Eyebrows and eyelashes were absent. Hearing loss was demonstrated. Psychomotor development was severely delayed. The patient suffered from recurrent severe bacterial and fungal skin infections, presenting as sharply circumscribed, hyperkeratotic and vegetating plaques. Death from septicemia occurred at the age of 1 year. Sbidian et al. (2010) identified a heterozygous G45E mutation in 4 sibs with the lethal form of KID syndrome, who were born of unrelated parents of African descent. Molecular studies indicated that the mother, who had palmoplantar keratosis, was germline mosaic for the mutation. Mese et al. (2011) found that expression of CX26 with the G45E mutation increased marker dye uptake in transfected HeLa cells and increased whole-cell membrane currents at both hyperpolarizing and depolarizing potentials in mouse N2A neuroblastoma cells. Transgenic Cx26 G45E mouse keratinocytes also showed increased whole-cell membrane currents at hyperpolarizing and depolarizing membrane potentials. Ogawa et al. (2014) reported a Japanese patient with KID due to a heterozygous G45E mutation in GJB2. The patient had inherited the mutant allele from her unaffected mother, who harbored both G45E and Y136X mutations in cis (121011.0042) in heterozygosity; however, in the patient the Y136X mutation was lost, thus allowing manifestation of the effects of the G45E mutation. Ogawa et al. (2014) stated that the G45E mutation is in complete linkage disequilibrium with Y136X in the Japanese population, and hypothesized that the Y136X mutation 'confines' and rescues the dominant pathogenic effect of the G45E mutation. (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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Comparative functional characterization of novel non-syndromic GJB2 gene variant p.Gly45Arg and lethal syndromic variant p.Gly45Glu. | Rodriguez-Paris J | PeerJ | 2016 | PMID: 27761313 |
Somatic Mosaicism for a "Lethal" GJB2 Mutation Results in a Patterned Form of Spiny Hyperkeratosis without Eccrine Involvement. | Eskin-Schwartz M | Pediatric dermatology | 2016 | PMID: 27087580 |
An effective screening strategy for deafness in combination with a next-generation sequencing platform: a consecutive analysis. | Sakuma N | Journal of human genetics | 2016 | PMID: 26763877 |
Revertant mutation releases confined lethal mutation, opening Pandora's box: a novel genetic pathogenesis. | Ogawa Y | PLoS genetics | 2014 | PMID: 24785414 |
The Cx26-G45E mutation displays increased hemichannel activity in a mouse model of the lethal form of keratitis-ichthyosis-deafness syndrome. | Mese G | Molecular biology of the cell | 2011 | PMID: 22031297 |
The clinical features of patients with the homozygous 235delC and the compound-heterozygous Y136X/G45E of the GJB2 mutations (Connexin 26) in cochlear implant recipients. | Yoshikawa S | Auris, nasus, larynx | 2011 | PMID: 21292415 |
Germline mosaicism in keratitis-ichthyosis-deafness syndrome: pre-natal diagnosis in a familial lethal form. | Sbidian E | Clinical genetics | 2010 | PMID: 20412116 |
Aberrant hemichannel properties of Cx26 mutations causing skin disease and deafness. | Gerido DA | American journal of physiology. Cell physiology | 2007 | PMID: 17428836 |
A novel mechanism for connexin 26 mutation linked deafness: cell death caused by leaky gap junction hemichannels. | Stong BC | The Laryngoscope | 2006 | PMID: 17146396 |
Simultaneous multigene mutation detection in patients with sensorineural hearing loss through a novel diagnostic microarray: a new approach for newborn screening follow-up. | Gardner P | Pediatrics | 2006 | PMID: 16950989 |
Cochleosaccular dysplasia associated with a connexin 26 mutation in keratitis-ichthyosis-deafness syndrome. | Griffith AJ | The Laryngoscope | 2006 | PMID: 16885744 |
GJB2 mutations in keratitis-ichthyosis-deafness syndrome including its fatal form. | Janecke AR | American journal of medical genetics. Part A | 2005 | PMID: 15633193 |
GJB2 deafness gene shows a specific spectrum of mutations in Japan, including a frequent founder mutation. | Ohtsuka A | Human genetics | 2003 | PMID: 12560944 |
Prevalent connexin 26 gene (GJB2) mutations in Japanese. | Abe S | Journal of medical genetics | 2000 | PMID: 10633133 |
Three novel connexin26 gene mutations in autosomal recessive non-syndromic deafness. | Fuse Y | Neuroreport | 1999 | PMID: 10501520 |
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Text-mined citations for rs72561723 ...
HelpRecord last updated Feb 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.
NCBI staff reviewed the sequence information reported in PubMed 20497192 Table 1 to determine the location of this allele on the current reference sequence.