ClinVar Genomic variation as it relates to human health
NM_004004.6(GJB2):c.385G>A (p.Glu129Lys)
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.385G>A (p.Glu129Lys)
Variation ID: 44747 Accession: VCV000044747.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q12.11 13: 20189197 (GRCh38) [ NCBI UCSC ] 13: 20763336 (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 Jan 31, 2015 Sep 29, 2024 Jun 18, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004004.6:c.385G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003995.2:p.Glu129Lys missense NC_000013.11:g.20189197C>T NC_000013.10:g.20763336C>T NG_008358.1:g.8779G>A LRG_1350:g.8779G>A LRG_1350t1:c.385G>A LRG_1350p1:p.Glu129Lys P29033:p.Glu129Lys - Protein change
- E129K
- Other names
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- Canonical SPDI
- NC_000013.11:20189196: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.
The Genome Aggregation Database (gnomAD) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00006
Exome Aggregation Consortium (ExAC) 0.00007
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 |
569 | 636 |
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
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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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Uncertain significance (1) |
criteria provided, multiple submitters, no conflicts
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May 26, 2023 | RCV000037849.6 | |
Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
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Jun 18, 2024 | RCV000730888.10 | |
Uncertain significance (2) |
criteria provided, single submitter
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Sep 12, 2017 | RCV001089545.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 31, 2020 | RCV001257047.1 |
Submissions - Germline
Classification
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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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Uncertain significance
(Dec 12, 2017)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000858655.1
First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Uncertain significance
(Sep 12, 2017)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 1A
Affected status: yes
Allele origin:
unknown
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Accession: SCV001244784.2
First in ClinVar: May 04, 2020 Last updated: Sep 16, 2020 |
Comment:
A heterozygous missense variant was identified, NM_004004.5(GJB2):c.385G>A in exon 2 of the GJB2 gene. This substitution creates a minor amino acid change from an glutamic … (more)
A heterozygous missense variant was identified, NM_004004.5(GJB2):c.385G>A in exon 2 of the GJB2 gene. This substitution creates a minor amino acid change from an glutamic acid to a lysine at position 129, NP_003995.2(GJB2):p.(Glu129Lys). The glutamic acid at this position has low conservation (100 vertebrates, UCSC). In silico predictions of the pathogenicity of this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). This variant has been previously observed in other deafness cases (Kenna, MA. et al. (2001), Dalamon, V. et al. (2005), Wu, B-L. et al. (2002) and Toth, T. et al. (2007)) and reported as PATHOGENIC in the Deafness Variation Database but evidence for its pathogenicity is conflicting and it is designated as a variant of uncertain significance in ClinVar. This variant is present in the gnomAD population database at a frequency of 0.0057% (14/245256, 0 hom). It is not situated in a known functional domain. The homozygous presence of the NM_004004.5(GJB2):c.101T>C variant in the same patient suggests that this variant (NM_004004.5(GJB2):c.385G>A) is in cis with one of the alleles. Based on current information, this variant has been classified as a VARIANT of UNKNOWN SIGNIFICANCE (VUS). (less)
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Uncertain significance
(Jun 18, 2024)
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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: SCV001802615.3
First in ClinVar: Aug 21, 2021 Last updated: Sep 29, 2024 |
Comment:
Observed multiple times in individuals with hearing loss; however, it is most commonly observed as heterozygous in cases of sporadic hearing loss where no other … (more)
Observed multiple times in individuals with hearing loss; however, it is most commonly observed as heterozygous in cases of sporadic hearing loss where no other GJB2 variant is identified (PMID: 15666300, 17671735, 24158611); Also observed on the opposite allele (in trans) from the c.35delG pathogenic variant in an individual without hearing loss (PMID: 21916817); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22695344, 11556849, 24158611, 25447126, 25388846, 24156272, 28483220, 19887791, 19081147, 19371219, 17666888, 15964725, 17671735, 25012701, 12172394, 12925341, 21916817, 30245029, 30275481, 33096615, 27169813, 15666300) (less)
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Uncertain significance
(May 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003933735.1
First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023 |
Comment:
Variant summary: GJB2 c.385G>A (p.Glu129Lys) results in a conservative amino acid change located in the Connexin, N-terminal (IPR013092) of the encoded protein sequence. Four of … (more)
Variant summary: GJB2 c.385G>A (p.Glu129Lys) results in a conservative amino acid change located in the Connexin, N-terminal (IPR013092) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 250484 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GJB2 causing Non-Syndromic Hearing Loss (6.4e-05 vs 0.00034), allowing no conclusion about variant significance. c.385G>A has been reported in the literature in heterozygous individuals affected with Non-Syndromic Hearing Loss (Example: Buonfiglio_2020, Dalamn_2005, Kenna_2001, Putcha_2007, Tth_2007, Wu_2002), and also observed in an unaffected child with a pathogenic variant (Chinetti_2011). These reports do not provide unequivocal conclusions about association of the variant with Non-Syndromic Hearing Loss. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33096615, 21916817, 15964725, 24158611, 11556849, 17666888, 17671735, 12172394).Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as uncertain significance citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Aug 31, 2020)
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criteria provided, single submitter
Method: clinical testing
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Nonsyndromic hearing loss and deafness
Affected status: yes
Allele origin:
germline
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INGEBI, INGEBI / CONICET
Accession: SCV001433598.1
First in ClinVar: Sep 27, 2020 Last updated: Sep 27, 2020 |
Comment:
Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the filtering allele frequency of c.385G>A, p.(Glu129Lys) variant in GJB2 gene is 0,00385% (4/35432 … (more)
Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the filtering allele frequency of c.385G>A, p.(Glu129Lys) variant in GJB2 gene is 0,00385% (4/35432 Latino alleles with 95%CI) from Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/) which meets the criteria to apply to PM2 rule. Computational evidence was not enough to neither apply to PP3 nor BP4 since REVEL score was 0.560. The p.(Glu129Lys) change has been identified in heterozygous state in six patients (PMID: 15666300, 17666888, 15964725, 11556849). In addition, it was reported (PMID: 11556849) that this variant could segregate in a dominant mode (data not shown) in patient with unilateral high frequency hearing loss and his affected father. However, since segregation analysis was not performed, this information was not counted. On the other hand, p.(Glu129Lys) has been identified in trans with a presumed pathogenic variant (p.Ala40Gly) (PMID: 19371219) meeting PM3 criteria. In summary, the clinical significance of this variant is currently uncertain (PM2, PM3). (less)
Number of individuals with the variant: 1
Clinical Features:
Prelingual profound bilateral hearing loss (present)
Family history: no
Sex: male
Ethnicity/Population group: Caucasian
Geographic origin: Argentina
Tissue: blood
Secondary finding: no
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Uncertain significance
(Mar 29, 2022)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003442047.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 129 of the GJB2 protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 129 of the GJB2 protein (p.Glu129Lys). This variant is present in population databases (rs397516875, gnomAD 0.01%). This missense change has been observed in individual(s) with GJB2-related conditions (PMID: 19371219, 33096615). ClinVar contains an entry for this variant (Variation ID: 44747). 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 GJB2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain Significance
(Jun 30, 2022)
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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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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000061511.6
First in ClinVar: May 03, 2013 Last updated: Apr 20, 2024 |
Comment:
The p.Glu129Lys variant in GJB2 has been reported in 5 individuals with sensorineural hearing loss (Kenna 2001, Dalamón 2005, Najmabadi 2005, Primignani 2009, Putcha 2007). … (more)
The p.Glu129Lys variant in GJB2 has been reported in 5 individuals with sensorineural hearing loss (Kenna 2001, Dalamón 2005, Najmabadi 2005, Primignani 2009, Putcha 2007). Only 1 of these individuals had a variant on the other allele, though the one other variant (Ala40Gly) is also of unknown significance. In another family, both the father and proband had unilateral high frequency sensorineural hearing loss raising the possibility of a dominant pattern of inheritance (Kenna 2001) though this is not consistent with the other 4 cases in the literature. This variant has not been identified in large and broad ethnically-matched populations by NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS). Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, additional data is needed to determine the clinical significance of this variant; however, given the absence of clear disease-causing variants on the second allele of any of the reported case, we would lean towards a more likely benign interpretation. ACMG/AMP Criteria applied: BP2. (less)
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Uncertain significance
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Autosomal recessive deafness type 1A
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001463370.1
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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GJB2 and GJB6 Genetic Variant Curation in an Argentinean Non-Syndromic Hearing-Impaired Cohort. | Buonfiglio P | Genes | 2020 | PMID: 33096615 |
Identification of four novel connexin 26 mutations in non-syndromic deaf patients: genotype-phenotype analysis in moderate cases. | Dalamón V | Molecular biology reports | 2013 | PMID: 24158611 |
Mutational analysis for GJB2, GJB6, and GJB3 genes in Campania within a universal neonatal hearing screening programme. | Chinetti V | International journal of audiology | 2011 | PMID: 21916817 |
Analysis of the GJB2 and GJB6 genes in Italian patients with nonsyndromic hearing loss: frequencies, novel mutations, genotypes, and degree of hearing loss. | Primignani P | Genetic testing and molecular biomarkers | 2009 | PMID: 19371219 |
Coincidence of mutations in different connexin genes in Hungarian patients. | Tóth T | International journal of molecular medicine | 2007 | PMID: 17671735 |
A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort. | Putcha GV | Genetics in medicine : official journal of the American College of Medical Genetics | 2007 | PMID: 17666888 |
Prevalence of GJB2 mutations and the del(GJB6-D13S1830) in Argentinean non-syndromic deaf patients. | Dalamón V | Hearing research | 2005 | PMID: 15964725 |
GJB2 mutations: passage through Iran. | Najmabadi H | American journal of medical genetics. Part A | 2005 | PMID: 15666300 |
Effectiveness of sequencing connexin 26 (GJB2) in cases of familial or sporadic childhood deafness referred for molecular diagnostic testing. | Wu BL | Genetics in medicine : official journal of the American College of Medical Genetics | 2002 | PMID: 12172394 |
Connexin 26 studies in patients with sensorineural hearing loss. | Kenna MA | Archives of otolaryngology--head & neck surgery | 2001 | PMID: 11556849 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GJB2 | - | - | - | - |
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Text-mined citations for rs397516875 ...
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.