ClinVar Genomic variation as it relates to human health
NM_004004.6(GJB2):c.508_511dup (p.Ala171fs)
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.508_511dup (p.Ala171fs)
Variation ID: 189070 Accession: VCV000189070.44
- Type and length
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Duplication, 4 bp
- Location
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Cytogenetic: 13q12.11 13: 20189070-20189071 (GRCh38) [ NCBI UCSC ] 13: 20763209-20763210 (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 Mar 16, 2024 Dec 14, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004004.6:c.508_511dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003995.2:p.Ala171fs frameshift NM_004004.6:c.508_511dupAACG MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_004004.5:c.508_511dupAACG NC_000013.11:g.20189071_20189074dup NC_000013.10:g.20763210_20763213dup NG_008358.1:g.8902_8905dup LRG_1350:g.8902_8905dup LRG_1350t1:c.508_511dup LRG_1350p1:p.Ala171fs - Protein change
- A171fs
- Other names
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- Canonical SPDI
- NC_000013.11:20189070:CGTT:CGTTCGTT
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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.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00004
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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
Help
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
Help
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 |
556 | 619 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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 (8) |
criteria provided, multiple submitters, no conflicts
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Jun 2, 2023 | RCV000169473.18 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Dec 14, 2023 | RCV000498375.15 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 14, 2022 | RCV002492693.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 10, 2021 | RCV001814083.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 27, 2023 | RCV003965220.1 |
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
Help
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
(Feb 08, 2013)
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criteria provided, single submitter
Method: clinical testing
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Deafness, autosomal recessive 1A
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000247476.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
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Pathogenic
(May 09, 2017)
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criteria provided, single submitter
Method: clinical testing
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Deafness, autosomal recessive 1A
Affected status: yes
Allele origin:
germline
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Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000599756.1
First in ClinVar: Sep 19, 2017 Last updated: Sep 19, 2017 |
Number of individuals with the variant: 1
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Pathogenic
(Apr 13, 2017)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 1A
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000698264.1
First in ClinVar: Sep 19, 2017 Last updated: Sep 19, 2017 |
Comment:
Variant summary: The GJB2 c.508_511dupAACG (p.Ala171Glufs) variant results in a premature termination codon, predicted to cause a truncated or absent GJB2 protein due to nonsense … (more)
Variant summary: The GJB2 c.508_511dupAACG (p.Ala171Glufs) variant results in a premature termination codon, predicted to cause a truncated or absent GJB2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One truncation downstream of this position has been classified as pathogenic by our laboratory (c.647_650delGATA/ p.Arg216fs). One in silico tool predicts a damaging outcome for this variant. The variant of interest has been found in a large, broad control population, ExAC in 2/121034 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.0003376). This variant has been reported in multiple studies, in Chinese and Koreean populations with NSHL in the compound heterozygous and homozygous state (Zhu_2015, Kim_2015, Jiang_2014). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic. (less)
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Pathogenic
(Jul 20, 2016)
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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: SCV000701343.2
First in ClinVar: Apr 02, 2018 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
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Pathogenic
(Jul 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Ear malformation
Affected status: yes
Allele origin:
germline
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Kariminejad - Najmabadi Pathology & Genetics Center
Accession: SCV001755334.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
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Likely pathogenic
(Nov 25, 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: SCV000220917.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
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Pathogenic
(Dec 19, 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: SCV000589636.5
First in ClinVar: Aug 20, 2017 Last updated: Dec 31, 2022 |
Comment:
Frameshift variant predicted to result in protein truncation, as the last 56 amino acids are lost and replaced with 39 incorrect amino acids (HGMD); This … (more)
Frameshift variant predicted to result in protein truncation, as the last 56 amino acids are lost and replaced with 39 incorrect amino acids (HGMD); This variant is associated with the following publications: (PMID: 24737404, 12172394, 16712961, 25587757, 26004784, 27247933, 27792752, 26783197, 17444514, 25891447, 24256046, 23638949, 22335977, 22695344, 28717060, 29926981, 31160754, 29871260) (less)
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Pathogenic
(Jan 14, 2022)
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criteria provided, single submitter
Method: clinical testing
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Mutilating keratoderma
Autosomal dominant keratitis-ichthyosis-hearing loss syndrome Palmoplantar keratoderma-deafness syndrome Knuckle pads, deafness AND leukonychia syndrome Autosomal recessive nonsyndromic hearing loss 1A X-linked mixed hearing loss with perilymphatic gusher Autosomal dominant nonsyndromic hearing loss 3A Ichthyosis, hystrix-like, with hearing loss
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002803888.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jun 02, 2023)
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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:
germline
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Integrating Genomics into Medicine, Frazer Institute, University Of Queensland
Accession: SCV003935275.1
First in ClinVar: Jul 01, 2023 Last updated: Jul 01, 2023 |
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Pathogenic
(Dec 14, 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: SCV001225144.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Ala171Glufs*40) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Ala171Glufs*40) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 56 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs773528125, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with autosomal recessive deafness (PMID: 12172394, 25891447). This variant is also known as 511-512insAACG. ClinVar contains an entry for this variant (Variation ID: 189070). This variant disrupts a region of the GJB2 protein in which other variant(s) (p.Cys211Leufs*5) have been determined to be pathogenic (PMID: 9529365, 12910486, 20863150). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jul 22, 2021)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 1A
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV001810445.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Sex: mixed
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Pathogenic
(Oct 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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GJB2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004783241.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The GJB2 c.508_511dupAACG variant is predicted to result in a frameshift and premature protein termination (p.Ala171Glufs*40). This variant has been reported in multiple individuals with … (more)
The GJB2 c.508_511dupAACG variant is predicted to result in a frameshift and premature protein termination (p.Ala171Glufs*40). This variant has been reported in multiple individuals with non-syndromic hearing loss (see for example, Table 1, Wu et al. 2002. PubMed ID: 12172394; Table 4, Jiang et al. 2014. PubMed ID: 24737404; Table S3, Yuan et al. 2019. PubMed ID: 31541171). This variant is reported in 0.030% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-20763209-G-GCGTT). Frameshift variants in GJB2 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
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Pathogenic
(Feb 26, 2019)
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no assertion criteria provided
Method: case-control
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Autosomal recessive nonsyndromic hearing loss 1A
Affected status: yes
Allele origin:
inherited
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Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital
Accession: SCV000902320.1
First in ClinVar: May 13, 2019 Last updated: May 13, 2019 |
Number of individuals with the variant: 32
Clinical Features:
hearing loss (present)
Family history: yes
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Pathogenic
(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: SCV001463361.1
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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Residual Hearing in DFNB1 Deafness and Its Clinical Implication in a Korean Population. | Kim SY | PloS one | 2015 | PMID: 26061264 |
The deafness-causing mutation c.508_511dup in the GJB2 gene and a literature review. | Zhu YM | Acta oto-laryngologica | 2015 | PMID: 25891447 |
Prevalence and range of GJB2 and SLC26A4 mutations in patients with autosomal recessive non‑syndromic hearing loss. | Jiang H | Molecular medicine reports | 2014 | PMID: 24737404 |
Prevalence of GJB2 mutations in the Silk Road region of China and a report of three novel variants. | Du W | Acta oto-laryngologica | 2014 | PMID: 24256046 |
Novel mutations of SLC26A4 in Chinese patients with nonsyndromic hearing loss. | Yao G | Acta oto-laryngologica | 2013 | PMID: 23638949 |
Impaired membrane targeting and aberrant cellular localization of human Cx26 mutants associated with inherited recessive hearing loss. | Xiao Z | Acta oto-laryngologica | 2011 | PMID: 20863150 |
Use of a multiplex PCR/sequencing strategy to detect both connexin 30 (GJB6) 342 kb deletion and connexin 26 (GJB2) mutations in cases of childhood deafness. | Wu BL | American journal of medical genetics. Part A | 2003 | PMID: 12910486 |
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 |
Novel mutations in the connexin 26 gene (GJB2) that cause autosomal recessive (DFNB1) hearing loss. | Kelley PM | American journal of human genetics | 1998 | PMID: 9529365 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GJB2 | - | - | - | - |
Text-mined citations for rs773528125 ...
HelpRecord last updated Mar 17, 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.