ClinVar Genomic variation as it relates to human health
NM_004004.6(GJB2):c.334_335del (p.Lys112fs)
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.334_335del (p.Lys112fs)
Variation ID: 189051 Accession: VCV000189051.17
- Type and length
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Deletion, 2 bp
- Location
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Cytogenetic: 13q12.11 13: 20189247-20189248 (GRCh38) [ NCBI UCSC ] 13: 20763386-20763387 (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 Jan 9, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004004.6:c.334_335del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003995.2:p.Lys112fs frameshift NM_004004.6:c.334_335delAA MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_004004.5:c.333_334delAA NC_000013.11:g.20189248_20189249del NC_000013.10:g.20763387_20763388del NG_008358.1:g.8728_8729del LRG_1350:g.8728_8729del LRG_1350t1:c.334_335del LRG_1350p1:p.Lys112fs - Protein change
- K112fs
- Other names
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- Canonical SPDI
- NC_000013.11:20189246:TTT: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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GJB2 | Dosage sensitivity unlikely | No evidence available |
GRCh38 GRCh37 |
556 | 619 |
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 (3) |
criteria provided, multiple submitters, no conflicts
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May 9, 2017 | RCV000169446.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 9, 2016 | RCV000616234.4 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 9, 2024 | RCV000517108.10 | |
Pathogenic (1) |
no assertion criteria provided
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Mar 21, 2013 | RCV000678879.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 21, 2020 | RCV001257562.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 22, 2022 | RCV002222422.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 18, 2021 | RCV002498844.1 |
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
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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
(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: SCV000599745.1
First in ClinVar: Sep 19, 2017 Last updated: Sep 19, 2017 |
Number of individuals with the variant: 1
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Pathogenic
(Jun 19, 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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Athena Diagnostics Inc
Accession: SCV000613513.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
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Pathogenic
(Jun 09, 2016)
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criteria provided, single submitter
Method: clinical testing
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Rare genetic deafness
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000710860.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
The p.Lys112fs variant in GJB2 has been reported in eight individuals with heari ng loss (Kelley 1998, Wu 2002, Putcha 2007, Nishio 2015). One of … (more)
The p.Lys112fs variant in GJB2 has been reported in eight individuals with heari ng loss (Kelley 1998, Wu 2002, Putcha 2007, Nishio 2015). One of these individua ls and their sibling were compound heterozygous for this variant and a second pa thogenic GJB2 variant (Kelley 1998). This variant is predicted to cause a frames hift, which alters the protein?s amino acid sequence beginning at position 112 a nd leads to a premature termination codon 2 amino acids downstream. This alterat ion is then predicted to lead to a truncated or absent protein. Loss of function of the GJB2 gene is an established disease mechanism in autosomal recessive hea ring loss. In summary, this variant meets the criteria to be classified as patho genic for autosomal recessive hearing loss based on its presence in compound het erozygosity with a known pathogenic variant in an affected individual and the pr edicted impact of the variant. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Nov 07, 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: SCV000220865.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
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Pathogenic
(Aug 21, 2020)
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criteria provided, single submitter
Method: clinical testing
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Nonsyndromic hearing loss and deafness
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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INGEBI, INGEBI / CONICET
Accession: SCV001434016.1
First in ClinVar: Oct 02, 2020 Last updated: Oct 02, 2020 |
Comment:
Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the c.334_335del variant which leads to p.(Lys112Glufs*2) in the GJB2 gene is present in … (more)
Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the c.334_335del variant which leads to p.(Lys112Glufs*2) in the GJB2 gene is present in only 1/34582 Latino alleles in Genome Aggregation Database (http://gnomad.broadinstitute.org); meeting the PM2 criteria. The c.334_335del variant is predicted to cause a premature stop codon in the only exon of GJB2 that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism (PVS1). This variant was detected in trans with 2 different pathogenic or suspected pathogenic variants in at least 4 hearing loss patients (PMID: 9529365, 21465647, 22695344, 23141775) applying to PM3_VeryStrong. Two familial cases with two affected siblings in each one showed segregation of the genotypes: c.[334_335del];[35delG] and c.[334_335del];[638T>A] in the affected siblings respectively applying to PP1_Moderate rule (PMID: 9529365, 23141775) In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss: PM2, PVS1, PM3_VeryStrong, PP1_Moderate. (less)
Number of individuals with the variant: 2
Clinical Features:
Congenital profound bilateral hearing loss (present)
Family history: yes
Sex: male
Ethnicity/Population group: Caucasian
Geographic origin: Argentina
Tissue: blood
Secondary finding: no
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Pathogenic
(Mar 22, 2022)
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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: SCV002500583.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Comment:
Variant summary: GJB2 c.334_335delAA (p.Lys112GlufsX2) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: GJB2 c.334_335delAA (p.Lys112GlufsX2) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 250258 control chromosomes. c.334_335delAA has been reported in the literature in multiple individuals affected with Autosomal Recessive Non-Syndromic Hearing Loss, and has been shown to segregate with disease in several families. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Nov 18, 2021)
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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: SCV002807439.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Apr 12, 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: SCV001829601.3
First in ClinVar: Sep 08, 2021 Last updated: Mar 04, 2023 |
Comment:
Observed in other patients with hearing loss in published literature (Putcha et al., 2007; Dodson et al., 2011; Atik et al., 2015); Frameshift variant predicted … (more)
Observed in other patients with hearing loss in published literature (Putcha et al., 2007; Dodson et al., 2011; Atik et al., 2015); Frameshift variant predicted to result in protein truncation, as the last 115 amino acids are lost and replaced with 1 incorrect amino acid, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database; This variant is associated with the following publications: (PMID: 31215297, 26561413, 27177978, 23141775, 9529365, 26990548, 21465647, 25587757, 22695344, 17666888, 12172394, 29257206, 27941975, 33096615, 31589614) (less)
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Pathogenic
(Jan 09, 2024)
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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: SCV001590824.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Lys112Glufs*2) 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.Lys112Glufs*2) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 115 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs756484720, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with non-syndromic deafness (PMID: 9529365, 23141775). It has also been observed to segregate with disease in related individuals. This variant is also known as c.333-334delAA. ClinVar contains an entry for this variant (Variation ID: 189051). This variant disrupts a region of the GJB2 protein in which other variant(s) (p.Gln124*) have been determined to be pathogenic (PMID: 9600457). 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
(Mar 21, 2013)
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no assertion criteria provided
Method: clinical testing
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Hearing loss
Affected status: yes
Allele origin:
germline
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Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital
Accession: SCV000805072.1
First in ClinVar: Sep 14, 2018 Last updated: Sep 14, 2018 |
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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: SCV001453337.1
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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Evaluation of electrocardiographic parameters in patients with hearing loss genotyped for the connexin 26 gene (GJB2) mutations. | Sanecka A | Brazilian journal of otorhinolaryngology | 2017 | PMID: 27177978 |
NGS-Based Assay for the Identification of Individuals Carrying Recessive Genetic Mutations in Reproductive Medicine. | Abulí A | Human mutation | 2016 | PMID: 26990548 |
Comprehensive Analysis of Deafness Genes in Families with Autosomal Recessive Nonsyndromic Hearing Loss. | Atik T | PloS one | 2015 | PMID: 26561413 |
Clinical application of a custom AmpliSeq library and ion torrent PGM sequencing to comprehensive mutation screening for deafness genes. | Nishio SY | Genetic testing and molecular biomarkers | 2015 | PMID: 25587757 |
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 |
A novel p.Leu213X mutation in GJB2 gene in a Portuguese family. | Gonçalves AC | International journal of pediatric otorhinolaryngology | 2013 | PMID: 23141775 |
The spectrum of GJB2 mutations in the Iranian population with non-syndromic hearing loss--a twelve year study. | Bazazzadegan N | International journal of pediatric otorhinolaryngology | 2012 | PMID: 22695344 |
Vestibular dysfunction in DFNB1 deafness. | Dodson KM | American journal of medical genetics. Part A | 2011 | PMID: 21465647 |
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 |
Mutation analysis of the GJB2 (connexin 26) gene in Egypt. | Snoeckx RL | Human mutation | 2005 | PMID: 15954104 |
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 |
Identification of mutations in the connexin 26 gene that cause autosomal recessive nonsyndromic hearing loss. | Scott DA | Human mutation | 1998 | PMID: 9600457 |
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 |
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Text-mined citations for rs756484720 ...
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.