ClinVar Genomic variation as it relates to human health
NM_004004.6(GJB2):c.313_326del (p.Lys105fs)
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.313_326del (p.Lys105fs)
Variation ID: 44737 Accession: VCV000044737.67
- Type and length
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Deletion, 14 bp
- Location
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Cytogenetic: 13q12.11 13: 20189256-20189269 (GRCh38) [ NCBI UCSC ] 13: 20763395-20763408 (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 Apr 4, 2013 Mar 10, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004004.6:c.313_326del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003995.2:p.Lys105fs NM_004004.6:c.313_326delAAGTTCATCAAGGG MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NC_000013.11:g.20189258_20189271del NC_000013.10:g.20763397_20763410del NG_008358.1:g.8707_8720del LRG_1350:g.8707_8720del LRG_1350t1:c.313_326del LRG_1350p1:p.Lys105fs - Protein change
- K105fs
- Other names
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- Canonical SPDI
- NC_000013.11:20189255:CCCTTGATGAACTTCC:CC
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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.
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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
Help
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 (10) |
criteria provided, multiple submitters, no conflicts
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Dec 9, 2021 | RCV000037836.34 | |
Pathogenic (10) |
criteria provided, multiple submitters, no conflicts
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Jan 31, 2024 | RCV000080370.50 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Apr 12, 2021 | RCV000146016.16 | |
Pathogenic (1) |
criteria provided, single submitter
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May 4, 2017 | RCV000211774.13 | |
Pathogenic (1) |
no assertion criteria provided
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Nov 13, 2014 | RCV000678878.9 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV001004389.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 21, 2020 | RCV001257561.9 |
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
(Jan 13, 2015)
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criteria provided, single submitter
Method: clinical testing
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Hearing impairment
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000492741.1
First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014 |
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Pathogenic
(Nov 18, 2016)
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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: SCV000698245.1
First in ClinVar: Jan 06, 2018 Last updated: Jan 06, 2018 |
Comment:
Variant summary: The GJB2 c.313_326delAAGTTCATCAAGGG (p.Lys105Glyfs) variant (alternatively also known as 313del14, 313-326del14, or 312del14) results in a premature termination codon, predicted to cause a … (more)
Variant summary: The GJB2 c.313_326delAAGTTCATCAAGGG (p.Lys105Glyfs) variant (alternatively also known as 313del14, 313-326del14, or 312del14) results in a premature termination codon, predicted to cause a truncated or absent GJB2 protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. If NMD is escaped, this variant is expected to truncate gap junction protein, cysteine-rich domain and connexin, N-terminal domain (InterPro).Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Gln124X, p.Gln164X, c.647_650delGAGA, etc.). This variant was found in 12/121692 control chromosomes at a frequency of 0.0000986, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). This variant is recurrently reported in patients with autosomal recessive NSHL and is reported to have hearing loss less severe than the c.35delG homozygotes (Kupka_2002, Wu_2002, Cryns_2004, Marlin_2005). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic. (less)
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Pathogenic
(May 04, 2017)
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criteria provided, single submitter
Method: clinical testing
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Rare genetic deafness
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000061498.5
First in ClinVar: May 03, 2013 Last updated: Apr 09, 2018 |
Comment:
The p.Lys105fs variant in GJB2 is a well-known pathogenic variant and has been i dentified in many individuals with hearing loss who were homozygous or … (more)
The p.Lys105fs variant in GJB2 is a well-known pathogenic variant and has been i dentified in many individuals with hearing loss who were homozygous or compound heterozygous with another pathogenic variant in GJB2 (Marlin 2005). It has been reported in 27/126134 European chromosomes and 10/20780 South Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/; dbSNP rs1 99976861). This frequency in the general population is consistent with the carri er frequency for autosomal recessive hearing loss. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 105 and leads to a premature termination codon 5 amino acids downstream . In summary, this variant meets criteria to be classified as pathogenic for aut osomal recessive hearing loss based on the predicted impact to the protein and m ultiple previously reported affected compound heterozygotes. ACMG/AMP Criteria a pplied: PVS1, PM3_VeryStrong. (less)
Number of individuals with the variant: 17
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 1A
Autosomal recessive nonsyndromic hearing loss 1B
Affected status: unknown
Allele origin:
germline
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Baylor Genetics
Accession: SCV001163361.1
First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020 |
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Pathogenic
(Oct 20, 2020)
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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 Inc
Accession: SCV000613512.2
First in ClinVar: Dec 06, 2016 Last updated: Sep 19, 2021 |
Comment:
This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with … (more)
This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. (less)
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Pathogenic
(Dec 09, 2021)
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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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MGZ Medical Genetics Center
Accession: SCV002579735.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
Number of individuals with the variant: 2
Sex: female
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Pathogenic
(Feb 03, 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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000603830.5
First in ClinVar: Sep 30, 2017 Last updated: Dec 24, 2022 |
Comment:
The GJB2 c.313_326del; p.Lys105GlyfsTer5 variant (rs111033253) is reported in the literature in individuals affected with hearing loss, both in the homozygous state and in trans … (more)
The GJB2 c.313_326del; p.Lys105GlyfsTer5 variant (rs111033253) is reported in the literature in individuals affected with hearing loss, both in the homozygous state and in trans to other pathogenic variants (Dalamon 2013, Denoyelle 1999, Kupa 2002, Mikstiene 2016). This variant is reported as pathogenic by numerous laboratories in ClinVar (Variation ID: 44737) and it is found in the general population with an overall allele frequency of 0.01% (38/281690 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting 14 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, the c.313_326del variant is considered to be pathogenic. References: Dalamon V et al. Identification of four novel connexin 26 mutations in non-syndromic deaf patients: genotype-phenotype analysis in moderate cases. Mol Biol Rep. 2013 Dec;40(12):6945-55. PMID: 24158611. Denoyelle F et al. Clinical features of the prevalent form of childhood deafness, DFNB1, due to a connexin-26 gene defect: implications for genetic counselling. Lancet. 1999 Apr 17;353(9161):1298-303. PMID: 10218527. Kupka S et al. Frequencies of GJB2 mutations in German control individuals and patients showing sporadic non-syndromic hearing impairment. Hum Mutat. 2002 Jul;20(1):77-8. PMID: 12112666. Mikstiene V et al. The high frequency of GJB2 gene mutation c.313_326del14 suggests its possible origin in ancestors of Lithuanian population. BMC Genet. 2016 Feb 19;17:45. PMID: 26896187. (less)
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Pathogenic
(Oct 19, 2021)
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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: SCV000329860.8
First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation, as the last 122 amino acids are lost and replaced with 4 incorrect amino acids (Stenson et … (more)
Frameshift variant predicted to result in protein truncation, as the last 122 amino acids are lost and replaced with 4 incorrect amino acids (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 22975760, 30094485, 10218527, 27224056, 25999548, 22567152, 29701678, 30168495, 30344259, 9529365, 29625052, 31980526, 31160754, 33096615, 31589614, 32067424, 26896187) (less)
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Pathogenic
(Sep 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001245650.19
First in ClinVar: May 09, 2020 Last updated: Mar 10, 2024 |
Comment:
GJB2: PM3:Very Strong, PVS1, PM2
Number of individuals with the variant: 7
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Pathogenic
(Feb 08, 2013)
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criteria provided, single submitter
Method: clinical testing
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Hearing impairment
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000193167.1
First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014 |
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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: no, yes
Allele origin:
germline
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Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000599744.1
First in ClinVar: Sep 19, 2017 Last updated: Sep 19, 2017 |
Observation 1:
Number of individuals with the variant: 3
Observation 2:
Number of individuals with the variant: 1
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Pathogenic
(Aug 15, 2018)
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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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Illumina Laboratory Services, Illumina
Accession: SCV000914614.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The GJB2 c.313_326delAAGTTCATCAAGGG (p.Lys105GlyfsTer5) variant results in a frameshift and is predicted to result in premature termination of the protein. Across a selection of the … (more)
The GJB2 c.313_326delAAGTTCATCAAGGG (p.Lys105GlyfsTer5) variant results in a frameshift and is predicted to result in premature termination of the protein. Across a selection of the available literature, the p.Lys105GlyfsTer5 variant has been identified in a total of 59 individuals with autosomal recessive nonsyndromic hearing loss including 18 homozygotes and 41 compound heterozygotes (Denoyelle et al. 1999; Marlin et al. 2005; Bazazzadegan et al 2012; Mikstiene et al. 2016). Thirty-seven of the compound heterozygotes carry c.35delG, a well known pathogenic variant, on the second allele. The p.Lys105GlyfsTer5 variant was found in a heterozygous state in two control individuals and is reported at a frequency of 0.00032 in the South Asian population of the Genome Aggregation Database. Based on the collective evidence and potential impact of frameshift variants, the p.Lys105GlyfsTer5 variant is classified as pathogenic for autosomal recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Feb 11, 2015)
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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: SCV000700403.2
First in ClinVar: Apr 02, 2018 Last updated: Jul 31, 2019 |
Number of individuals with the variant: 10
Sex: mixed
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Pathogenic
(Dec 26, 2019)
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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:
unknown
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Myriad Genetics, Inc.
Accession: SCV001194006.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 03, 2020 |
Comment:
NM_004004.5(GJB2):c.313_326del14(K105Gfs*5) is classified as pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. Sources cited for classification include the following: PMID 22567152. … (more)
NM_004004.5(GJB2):c.313_326del14(K105Gfs*5) is classified as pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. Sources cited for classification include the following: PMID 22567152. Classification of NM_004004.5(GJB2):c.313_326del14(K105Gfs*5) is based on the following criteria: The variant causes a premature termination codon that is not expected to be targeted by nonsense-mediated mRNA decay; however, literature evidence strongly supports pathogenicity. Please note: this variant was assessed in the context of healthy population screening. (less)
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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: SCV001434015.1
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 filtering allele frequency of the c.313_326del (p.Lys105fs*5) variant in the GJB2 gene is … (more)
Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the filtering allele frequency of the c.313_326del (p.Lys105fs*5) variant in the GJB2 gene is 0,015% (9/30614 South Asian alleles with 95% CI) in Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which meets the PM2_Supporting criteria. The c.313_326del 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 has been detected in trans with at least 4 pathogenic variants in different hearing loss patients (PMID: 10218527, 10982180, 11551103, 24158611, 27224056) applying to PM3_VeryStrong. This variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss: PM2_Supporting, PVS1, PM3_VeryStrong. (less)
Number of individuals with the variant: 2
Clinical Features:
Prelingual moderate bilateral hearing loss (present)
Family history: no
Sex: female
Ethnicity/Population group: Caucasian
Geographic origin: Argentina
Tissue: blood
Secondary finding: no
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Pathogenic
(Jan 13, 2017)
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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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Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001449875.1
First in ClinVar: Dec 10, 2020 Last updated: Dec 10, 2020 |
Number of individuals with the variant: 1
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Likely pathogenic
(Apr 12, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hearing impairment
Affected status: yes
Allele origin:
germline
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Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center
Accession: SCV001571779.2
First in ClinVar: May 01, 2021 Last updated: Aug 21, 2021 |
Comment:
PVS1_Strong, PM2_Moderate, PM3_Moderate
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Pathogenic
(Apr 12, 2021)
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criteria provided, single submitter
Method: research
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Autosomal recessive nonsyndromic hearing loss 1A
Affected status: yes
Allele origin:
maternal
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HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: AGHI WGS
Accession: SCV001870363.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
Comment:
ACMG codes:PVS1, PM2, PP5
Number of individuals with the variant: 1
Clinical Features:
Bilateral sensorineural hearing impairment (present) , Attention deficit hyperactivity disorder (present) , Downslanted palpebral fissures (present) , Intellectual disability (present)
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Pathogenic
(Dec 17, 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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Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital
Accession: SCV002818209.1
First in ClinVar: Jan 07, 2023 Last updated: Jan 07, 2023 |
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Pathogenic
(Aug 31, 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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004225744.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PM2_supporting, PM3_very_strong, PVS1
Number of individuals with the variant: 1
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Pathogenic
(Mar 26, 2021)
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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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Revvity Omics, Revvity
Accession: SCV002024256.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 31, 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: SCV001227363.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Lys105Glyfs*5) 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.Lys105Glyfs*5) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 122 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs111033253, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with autosomal recessive deafness (PMID: 10218527, 22567152, 26896187, 27224056). ClinVar contains an entry for this variant (Variation ID: 44737). This variant disrupts the p.Pro173, p.Arg184 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10874298, 10982180, 15855033, 25708704). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Aug 01, 2004)
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no assertion criteria provided
Method: literature only
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DEAFNESS, AUTOSOMAL RECESSIVE 1A
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000038814.2
First in ClinVar: Apr 04, 2013 Last updated: May 09, 2020 |
Comment on evidence:
In 5 of 156 Czech patients with prelingual deafness (DFNB1A; 220290), Seeman et al. (2004) identified a 14-bp deletion at nucleotide 313 of the GJB2 … (more)
In 5 of 156 Czech patients with prelingual deafness (DFNB1A; 220290), Seeman et al. (2004) identified a 14-bp deletion at nucleotide 313 of the GJB2 gene. (less)
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Pathogenic
(Nov 13, 2014)
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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: SCV000805071.1
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: SCV001453338.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Pathogenic
(Jun 24, 2021)
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no assertion criteria provided
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 1A
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Clinical Genomics Program, Stanford Medicine
Accession: SCV004231803.1
First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024 |
Comment:
The p.Lys105Glyfs*5 variant in the GJB2 gene is a well reported cause of nonsyndromic hearing loss. This variant was determined to be in trans with … (more)
The p.Lys105Glyfs*5 variant in the GJB2 gene is a well reported cause of nonsyndromic hearing loss. This variant was determined to be in trans with other pathogenic variants (p.Gly12Valfs*2, p.Met34Thr), consistent with autosomal recessive inheritance (Marlin et al., 2005; Mikstiene et al., 2016). The presence of this variant with an established disease-causing variant on the opposite allele increases suspicion for its pathogenicity. The p.Lys105Glyfs*5 variant has also been identified in 9/30,614 South Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant results in a 14 bp deletion, which causes a shift in the protein reading frame, leading to a premature termination codon 5 amino acids downstream. Loss of function is an established mechanism of disease for the GJB2 gene. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Lys105Glyfs*5 variant as pathogenic for autosomal recessive nonsyndromic hearing loss based on the information above. [ACMG evidence codes used: PVS1; PM3_verystrong; PM2_supporting] (less)
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Pathogenic
(Jan 25, 2021)
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Flagged submission
flagged submission
Method: clinical testing
Reason: This record appears to be redundant with a more recent record from the same submitter.
Notes: SCV001984287 appears to be redundant with SCV002818209.
(less)
Notes: SCV001984287 appears to
(...more)
Source: NCBI
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Autosomal recessive nonsyndromic hearing loss 1A
Affected status: yes
Allele origin:
germline
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Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital
Accession: SCV001984287.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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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Spectrum and Frequency of the GJB2 Gene Pathogenic Variants in a Large Cohort of Patients with Hearing Impairment Living in a Subarctic Region of Russia (the Sakha Republic). | Barashkov NA | PloS one | 2016 | PMID: 27224056 |
The high frequency of GJB2 gene mutation c.313_326del14 suggests its possible origin in ancestors of Lithuanian population. | Mikstiene V | BMC genetics | 2016 | PMID: 26896187 |
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 |
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 |
Spectrum of genetic changes in patients with non-syndromic hearing impairment and extremely high carrier frequency of 35delG GJB2 mutation in Belarus. | Danilenko N | PloS one | 2012 | PMID: 22567152 |
Prevalence of the 35delG mutation in the GJB2 gene of patients with nonsyndromic hearing loss from Croatia. | Sansović I | Genetic testing | 2005 | PMID: 16379542 |
GJB2 and GJB6 mutations: genotypic and phenotypic correlations in a large cohort of hearing-impaired patients. | Marlin S | Archives of otolaryngology--head & neck surgery | 2005 | PMID: 15967879 |
GJB2 mutations in Turkish patients with ARNSHL: prevalence and two novel mutations. | Kalay E | Hearing research | 2005 | PMID: 15855033 |
Spectrum and frequencies of mutations in the GJB2 (Cx26) gene among 156 Czech patients with pre-lingual deafness. | Seeman P | Clinical genetics | 2004 | PMID: 15253766 |
GJB2 mutations in patients with non-syndromic hearing loss from Northeastern Hungary. | Tóth T | Human mutation | 2004 | PMID: 15146474 |
A genotype-phenotype correlation for GJB2 (connexin 26) deafness. | Cryns K | Journal of medical genetics | 2004 | PMID: 14985372 |
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 |
Frequencies of GJB2 mutations in German control individuals and patients showing sporadic non-syndromic hearing impairment. | Kupka S | Human mutation | 2002 | PMID: 12112666 |
High frequency of GJB2 gene mutations in Polish patients with prelingual nonsyndromic deafness. | Wiszniewski W | Genetic testing | 2001 | PMID: 11551103 |
Molecular basis of childhood deafness resulting from mutations in the GJB2 (connexin 26) gene. | Rabionet R | Human genetics | 2000 | PMID: 10982180 |
Mutation analysis of the GJB2 (connexin 26) gene by DGGE in Greek patients with sensorineural deafness. | Antoniadi T | Human mutation | 2000 | PMID: 10874298 |
Clinical features of the prevalent form of childhood deafness, DFNB1, due to a connexin-26 gene defect: implications for genetic counselling. | Denoyelle F | Lancet (London, England) | 1999 | PMID: 10218527 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GJB2 | - | - | - | - |
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Text-mined citations for rs111033253 ...
HelpRecord last updated Mar 23, 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.