ClinVar Genomic variation as it relates to human health
NM_004004.6(GJB2):c.670A>C (p.Lys224Gln)
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.670A>C (p.Lys224Gln)
Variation ID: 44765 Accession: VCV000044765.32
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q12.11 13: 20188912 (GRCh38) [ NCBI UCSC ] 13: 20763051 (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 9, 2018 Nov 11, 2023 Aug 24, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004004.6:c.670A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003995.2:p.Lys224Gln missense NC_000013.11:g.20188912T>G NC_000013.10:g.20763051T>G NG_008358.1:g.9064A>C LRG_1350:g.9064A>C LRG_1350t1:c.670A>C LRG_1350p1:p.Lys224Gln - Protein change
- K224Q
- Other names
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- Canonical SPDI
- NC_000013.11:20188911:T:G
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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.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Exome Aggregation Consortium (ExAC) 0.00009
The Genome Aggregation Database (gnomAD), exomes 0.00013
The Genome Aggregation Database (gnomAD) 0.00015
Trans-Omics for Precision Medicine (TOPMed) 0.00023
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 |
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Conditions - Germline
Condition
Help
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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Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Aug 24, 2023 | RCV000037870.19 | |
Uncertain significance (2) |
criteria provided, single submitter
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Mar 30, 2017 | RCV000666342.2 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Jan 24, 2023 | RCV000710115.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 12, 2021 | RCV000763879.3 |
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
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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
(Mar 30, 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:
unknown
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Counsyl
Accession: SCV000790618.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Uncertain significance
(Mar 23, 2018)
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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: SCV000613523.2
First in ClinVar: May 29, 2016 Last updated: Oct 19, 2018 |
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Uncertain significance
(Apr 04, 2018)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000061532.5
First in ClinVar: May 03, 2013 Last updated: Apr 09, 2018 |
Comment:
The p.Lys224Gln variant in GJB2 has been previously reported in 8 individuals wi th hearing loss (Antoniadi 2000, Pandya 2003, Samanich 2007, Kokotas 2010, Shan … (more)
The p.Lys224Gln variant in GJB2 has been previously reported in 8 individuals wi th hearing loss (Antoniadi 2000, Pandya 2003, Samanich 2007, Kokotas 2010, Shan 2010, LMM data); however a variant affecting the remaining DFNB1 allele (GJB2 a nd GJB6 genes) was not identified in any of the individuals. This variant has be en identified in 27/124038 European chromosomes and in 5/34358 Latino chromosome s by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs111033194), though, this frequency is not high enough to rule out a path ogenic role. Computational prediction tools and conservation analyses do not pro vide strong support for or against an impact to the protein. In summary, the cli nical significance of the p.Lys224Gln variant is uncertain. ACMG/AMP Criteria ap plied: None. (less)
Number of individuals with the variant: 7
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Uncertain significance
(Dec 24, 2018)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001156572.1
First in ClinVar: Feb 10, 2020 Last updated: Feb 10, 2020 |
Comment:
The GJB2 c.670A>C; p.Lys224Gln variant (rs111033194) is reported in the literature in individuals with hearing loss and in several normal-hearing controls (Antoniadi 2000, Matos 2011, … (more)
The GJB2 c.670A>C; p.Lys224Gln variant (rs111033194) is reported in the literature in individuals with hearing loss and in several normal-hearing controls (Antoniadi 2000, Matos 2011, Pandya 2003, Putcha 2007, Samanich 2007). This variant does not exhibit dominant inheritance (Antoniadi 2000), and, to our knowledge, it has not been reported in trans to another pathogenic variant in affected individuals (Antoniadi 2000, Pandya 2003, Putcha 2007, Samanich 2007). This variant is reported in ClinVar (Variation ID: 44765), and it is found in the general population with an overall allele frequency of 0.01% (36/279154 alleles) in the Genome Aggregation Database. The lysine at codon 224 is highly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Given the lack of clinical and functional data, the significance of the p.Lys224Gln variant is uncertain at this time. References: Antoniadi T et al. Mutation analysis of the GJB2 (connexin 26) gene by DGGE in Greek patients with sensorineural deafness. Hum Mutat. 2000;16(1):7-12. Matos TD et al. Assessing Noncoding Sequence Variants of GJB2 for Hearing Loss Association. Genet Res Int. 2011;2011:827469. Pandya A et al. Frequency and distribution of GJB2 (connexin 26) and GJB6 (connexin 30) mutations in a large North American repository of deaf probands. Genet Med. 2003 Jul-Aug;5(4):295-303. Putcha GV et al. A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort. Genet Med. 2007 Jul;9(7):413-26. Samanich J et al. Mutations in GJB2, GJB6, and mitochondrial DNA are rare in African American and Caribbean Hispanic individuals with hearing impairment. Am J Med Genet A. 2007 Apr 15;143A(8):830-8. (less)
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Uncertain significance
(Oct 12, 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: SCV000894814.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
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Uncertain significance
(Oct 12, 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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Invitae
Accession: SCV003292077.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 224 of the GJB2 protein (p.Lys224Gln). … (more)
This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 224 of the GJB2 protein (p.Lys224Gln). This variant is present in population databases (rs111033194, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive deafness (PMID: 17444514). ClinVar contains an entry for this variant (Variation ID: 44765). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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
(Jan 24, 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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GeneDx
Accession: SCV001875061.4
First in ClinVar: Sep 19, 2021 Last updated: Nov 11, 2023 |
Comment:
Observed in the heterozygous state without a second variant in multiple individuals with hearing loss in the published literature (Antoniadi et al., 2000; Pandya et … (more)
Observed in the heterozygous state without a second variant in multiple individuals with hearing loss in the published literature (Antoniadi et al., 2000; Pandya et al., 2003; Samanich et al., 2007; Shan et al., 2010); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19230829, 17357124, 12172392, 25262649, 25388846, 26990548, 30245029, 19081147, 26542351, 20059378, 17666888, 17366579, 16125251, 22567369, 21844220, 20381175, 12865758, 31620696, 33199029, 17444514, 10874298) (less)
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Uncertain significance
(Aug 24, 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: SCV000917434.2
First in ClinVar: Jun 02, 2019 Last updated: Oct 04, 2023 |
Comment:
Variant summary: GJB2 c.670A>C (p.Lys224Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign … (more)
Variant summary: GJB2 c.670A>C (p.Lys224Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 250298 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in GJB2 causing Autosomal Recessive Non-Syndromic Hearing Loss (0.00014 vs 0.025), allowing no conclusion about variant significance. c.670A>C has been reported in the literature in multiple individuals affected with non-syndromic hearing loss, including both heterozygous individuals without a second variant identified and homozygous individuals (Tekin_2007, Ozylmaz_2019) without evidence of cosegregation with disease provided. These reports do not provide unequivocal conclusions about association of the variant with Autosomal Recessive Non-Syndromic Hearing Loss. One publication reports experimental evidence evaluating an impact on protein function (Spagnol_2016), however it does not allow convincing conclusions about the variant effect. The following publications have been ascertained in the context of this evaluation (PMID: 17366579, 22567369, 12865758, 17666888, 19230829, 20381175, 23695287, 19081147, 17357124, 22016077, 10874298, 26542351, 31620696, 30245029). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Additionally, a published expert curation also classified the variant as uncertain significance (Deafness Variation Database, Azaiez_2018). Based on the evidence outlined above, the variant was classified as uncertain significance. (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: SCV001463357.1
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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First-Line Molecular Genetic Evaluation of Autosomal Recessive Non-Syndromic Hearing Loss. | Özyılmaz B | Turkish archives of otorhinolaryngology | 2019 | PMID: 31620696 |
Genomic Landscape and Mutational Signatures of Deafness-Associated Genes. | Azaiez H | American journal of human genetics | 2018 | PMID: 30245029 |
NGS-Based Assay for the Identification of Individuals Carrying Recessive Genetic Mutations in Reproductive Medicine. | Abulí A | Human mutation | 2016 | PMID: 26990548 |
Secondary structural analysis of the carboxyl-terminal domain from different connexin isoforms. | Spagnol G | Biopolymers | 2016 | PMID: 26542351 |
Bioinformatic Analysis of GJB2 Gene Missense Mutations. | Yilmaz A | Cell biochemistry and biophysics | 2015 | PMID: 25388846 |
Utilizing ethnic-specific differences in minor allele frequency to recategorize reported pathogenic deafness variants. | Shearer AE | American journal of human genetics | 2014 | PMID: 25262649 |
EMQN Best Practice guidelines for diagnostic testing of mutations causing non-syndromic hearing impairment at the DFNB1 locus. | Hoefsloot LH | European journal of human genetics : EJHG | 2013 | PMID: 23695287 |
Assessing Noncoding Sequence Variants of GJB2 for Hearing Loss Association. | Matos TD | Genetics research international | 2011 | PMID: 22567369 |
Deafness in the genomics era. | Shearer AE | Hearing research | 2011 | PMID: 22016077 |
Mechanism for modulation of gating of connexin26-containing channels by taurine. | Locke D | The Journal of general physiology | 2011 | PMID: 21844220 |
GJB2 mutation spectrum in 209 hearing impaired individuals of predominantly Caribbean Hispanic and African descent. | Shan J | International journal of pediatric otorhinolaryngology | 2010 | PMID: 20381175 |
Easy, rapid, and cost-effective methods for identifying carriers of recurrent GJB2 mutations causing nonsyndromic hearing impairment in the Greek population. | Kokotas H | Genetic testing and molecular biomarkers | 2010 | PMID: 20059378 |
Diverse deafness mechanisms of connexin mutations revealed by studies using in vitro approaches and mouse models. | Hoang Dinh E | Brain research | 2009 | PMID: 19230829 |
Genetic evaluation of American minority pediatric cochlear implant recipients. | Fischer TC | International journal of pediatric otorhinolaryngology | 2009 | PMID: 19081147 |
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 |
Genetic epidemiological studies of congenital/prelingual deafness in Turkey: population structure and mating type are major determinants of mutation identification. | Tekin M | American journal of medical genetics. Part A | 2007 | PMID: 17444514 |
Familial neonatal Marfan syndrome due to parental mosaicism of a missense mutation in the FBN1 gene. | Tekin M | American journal of medical genetics. Part A | 2007 | PMID: 17366579 |
Mutations in GJB2, GJB6, and mitochondrial DNA are rare in African American and Caribbean Hispanic individuals with hearing impairment. | Samanich J | American journal of medical genetics. Part A | 2007 | PMID: 17357124 |
Ethnicity and mutations in GJB2 (connexin 26) and GJB6 (connexin 30) in a multi-cultural Canadian paediatric Cochlear Implant Program. | Propst EJ | International journal of pediatric otorhinolaryngology | 2006 | PMID: 16125251 |
Frequency and distribution of GJB2 (connexin 26) and GJB6 (connexin 30) mutations in a large North American repository of deaf probands. | Pandya A | Genetics in medicine : official journal of the American College of Medical Genetics | 2003 | PMID: 12865758 |
GJB2 (connexin 26) variants and nonsyndromic sensorineural hearing loss: a HuGE review. | Kenneson A | Genetics in medicine : official journal of the American College of Medical Genetics | 2002 | PMID: 12172392 |
Mutation analysis of the GJB2 (connexin 26) gene by DGGE in Greek patients with sensorineural deafness. | Antoniadi T | Human mutation | 2000 | PMID: 10874298 |
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Text-mined citations for rs111033194 ...
HelpRecord last updated Jan 26, 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.