Published functional studies demonstrate a damaging effect with the variant resulting in gap junctions that are incapable of intercellular coupling (Matos et al., 2007); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19101659, 25266519, 12865758, 25388846, 16222667, 24774219, 23668481, 9529365, 31160754, 30344259, 34440441, 34652575, 36100214, 26553399, 17660464, 31992338, 32067424)
ClinVar Genomic variation as it relates to human health
NM_004004.6(GJB2):c.250G>A (p.Val84Met)
Germline
Classification
Help
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.
(11)
Help
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.
Pathogenic
11
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_004004.6(GJB2):c.250G>A (p.Val84Met)
Variation ID: 17036 Accession: VCV000017036.17
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 13q12.11 13: 20189332 (GRCh38) [ NCBI UCSC ] 13: 20763471 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Jun 1, 2016 Feb 14, 2024 Jan 25, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_004004.6:c.250G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003995.2:p.Val84Met missense NC_000013.11:g.20189332C>T NC_000013.10:g.20763471C>T NG_008358.1:g.8644G>A LRG_1350:g.8644G>A LRG_1350t1:c.250G>A LRG_1350p1:p.Val84Met P29033:p.Val84Met - Protein change
- V84M
- Other names
- -
- Canonical SPDI
- NC_000013.11:20189331:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| GJB2 | Dosage sensitivity unlikely | No evidence available |
GRCh38 GRCh37 |
570 | 637 | |
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. |
|---|---|---|---|---|
| Pathogenic (4) |
criteria provided, single submitter
|
Jun 2, 2023 | RCV000018564.29 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 25, 2024 | RCV000254760.9 | |
| Pathogenic (1) |
no assertion criteria provided
|
Feb 12, 2007 | RCV000211769.4 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 8, 2016 | RCV000410225.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 1, 2017 | RCV000626853.2 | |
|
GJB2-related disorder
|
Pathogenic (1) |
criteria provided, single submitter
|
Jun 21, 2023 | RCV004532387.2 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Jan 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Progressive sensorineural hearing impairment
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000747556.1
First in ClinVar: May 12, 2018 Last updated: May 12, 2018 |
|
|
|
Pathogenic
(Jun 08, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal dominant nonsyndromic hearing loss 3A
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000487630.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
|
|
|
Pathogenic
(May 19, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000322426.8
First in ClinVar: Oct 09, 2016 Last updated: Jun 17, 2023 |
Comment:
Published functional studies demonstrate a damaging effect with the variant resulting in gap junctions that are incapable of intercellular coupling (Matos et al., 2007); Not … (more)
Published functional studies demonstrate a damaging effect with the variant resulting in gap junctions that are incapable of intercellular coupling (Matos et al., 2007); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19101659, 25266519, 12865758, 25388846, 16222667, 24774219, 23668481, 9529365, 31160754, 30344259, 34440441, 34652575, 36100214, 26553399, 17660464, 31992338, 32067424) (less)
|
|
|
Pathogenic
(Jun 02, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 1A
Affected status: yes
Allele origin:
germline
|
Integrating Genomics into Medicine, Frazer Institute, University Of Queensland
Accession: SCV003935288.1
First in ClinVar: Jul 01, 2023 Last updated: Jul 01, 2023 |
|
|
|
Pathogenic
(Jun 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
GJB2-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004109658.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The GJB2 c.250G>A variant is predicted to result in the amino acid substitution p.Val84Met. This variant has been reported in the homozygous and compound heterozygous … (more)
The GJB2 c.250G>A variant is predicted to result in the amino acid substitution p.Val84Met. This variant has been reported in the homozygous and compound heterozygous states in patients with nonsyndromic hearing loss (Plevova. 2018. PubMed ID: 30344259; Pandya. 2020. PubMed ID: 32067424; Table S2, Shen. 2019. PubMed ID: 31160754; Zhang. 2011. PubMed ID: 21366436; Cheng. 2005. PubMed ID: 16222667; Martínez-Saucedo. 2015. PubMed ID: 26553399; Primignani. 2009. PubMed ID: 19371219; Loeza-Becerra. 2014. PubMed ID: 24774219). This variant is reported in 0.0099% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-20763471-C-T). This variant is interpreted as pathogenic. (less)
|
|
|
Pathogenic
(Aug 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV001143664.3
First in ClinVar: Jan 19, 2020 Last updated: Jan 26, 2024 |
Comment:
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 … (more)
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 hearing loss. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 17660464) 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)
|
|
|
Pathogenic
(Jan 25, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004295452.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 84 of the GJB2 protein (p.Val84Met). … (more)
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 84 of the GJB2 protein (p.Val84Met). This variant is present in population databases (rs104894409, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive non-syndromic deafness (PMID: 30344259, 31160754). ClinVar contains an entry for this variant (Variation ID: 17036). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GJB2 protein function with a positive predictive value of 95%. This variant disrupts the p.Val84 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11556849, 12172394, 16380907, 19235794). 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)
|
|
|
Pathogenic
(Nov 01, 2007)
|
no assertion criteria provided
Method: literature only
|
DEAFNESS, AUTOSOMAL RECESSIVE 1A
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000038846.3
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
For discussion of the val84-to-met (V84M) mutation in the GJB2 gene that was found in compound heterozygous state in a patient with autosomal recessive neurosensory … (more)
For discussion of the val84-to-met (V84M) mutation in the GJB2 gene that was found in compound heterozygous state in a patient with autosomal recessive neurosensory deafness (DFNB1A; 220290) by Matos et al. (2007), see 121011.0036. (less)
|
|
|
Pathogenic
(Feb 12, 2007)
|
no assertion criteria provided
Method: clinical testing
|
Rare genetic deafness
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000061491.4
First in ClinVar: May 03, 2013 Last updated: Jun 01, 2016 |
Number of individuals with the variant: 2
|
|
|
Pathogenic
(Jun 08, 2016)
|
no assertion criteria provided
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 1A
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000487629.2
First in ClinVar: Aug 22, 2016 Last updated: Aug 22, 2016 |
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Autosomal recessive deafness type 1A
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001453342.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
The GJB2 c.250G>A variant is predicted to result in the amino acid substitution p.Val84Met. This variant has been reported in the homozygous and compound heterozygous states in patients with nonsyndromic hearing loss (Plevova. 2018. PubMed ID: 30344259; Pandya. 2020. PubMed ID: 32067424; Table S2, Shen. 2019. PubMed ID: 31160754; Zhang. 2011. PubMed ID: 21366436; Cheng. 2005. PubMed ID: 16222667; Martínez-Saucedo. 2015. PubMed ID: 26553399; Primignani. 2009. PubMed ID: 19371219; Loeza-Becerra. 2014. PubMed ID: 24774219). This variant is reported in 0.0099% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-20763471-C-T). This variant is interpreted as pathogenic.
Comment:
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 hearing loss. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 17660464) 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.
Comment:
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 84 of the GJB2 protein (p.Val84Met). This variant is present in population databases (rs104894409, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive non-syndromic deafness (PMID: 30344259, 31160754). ClinVar contains an entry for this variant (Variation ID: 17036). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GJB2 protein function with a positive predictive value of 95%. This variant disrupts the p.Val84 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11556849, 12172394, 16380907, 19235794). 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.
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. |
Comment:
Published functional studies demonstrate a damaging effect with the variant resulting in gap junctions that are incapable of intercellular coupling (Matos et al., 2007); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19101659, 25266519, 12865758, 25388846, 16222667, 24774219, 23668481, 9529365, 31160754, 30344259, 34440441, 34652575, 36100214, 26553399, 17660464, 31992338, 32067424)
Comment:
The GJB2 c.250G>A variant is predicted to result in the amino acid substitution p.Val84Met. This variant has been reported in the homozygous and compound heterozygous states in patients with nonsyndromic hearing loss (Plevova. 2018. PubMed ID: 30344259; Pandya. 2020. PubMed ID: 32067424; Table S2, Shen. 2019. PubMed ID: 31160754; Zhang. 2011. PubMed ID: 21366436; Cheng. 2005. PubMed ID: 16222667; Martínez-Saucedo. 2015. PubMed ID: 26553399; Primignani. 2009. PubMed ID: 19371219; Loeza-Becerra. 2014. PubMed ID: 24774219). This variant is reported in 0.0099% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-20763471-C-T). This variant is interpreted as pathogenic.
Comment:
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 hearing loss. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 17660464) 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.
Comment:
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 84 of the GJB2 protein (p.Val84Met). This variant is present in population databases (rs104894409, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive non-syndromic deafness (PMID: 30344259, 31160754). ClinVar contains an entry for this variant (Variation ID: 17036). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GJB2 protein function with a positive predictive value of 95%. This variant disrupts the p.Val84 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11556849, 12172394, 16380907, 19235794). 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Analyses of del(GJB6-D13S1830) and del(GJB6-D13S1834) deletions in a large cohort with hearing loss: Caveats to interpretation of molecular test results in multiplex families. | Pandya A | Molecular genetics & genomic medicine | 2020 | PMID: 32067424 |
| Consensus interpretation of the p.Met34Thr and p.Val37Ile variants in GJB2 by the ClinGen Hearing Loss Expert Panel. | Shen J | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 31160754 |
| Genetic Aetiology of Nonsyndromic Hearing Loss in Moravia-Silesia. | Plevova P | Medicina (Kaunas, Lithuania) | 2018 | PMID: 30344259 |
| Two novel compound heterozygous families with a trimutation in the GJB2 gene causing sensorineural hearing loss. | Martínez-Saucedo M | International journal of pediatric otorhinolaryngology | 2015 | PMID: 26553399 |
| Bioinformatic Analysis of GJB2 Gene Missense Mutations. | Yilmaz A | Cell biochemistry and biophysics | 2015 | PMID: 25388846 |
| Comparative study of mutation spectrums of MT-RNR1 m.1555A>G, GJB2, and SLC26A4 between familial and sporadic patients with nonsyndromic sensorineural hearing loss in Chinese Han. | Li Q | Chinese medical journal | 2014 | PMID: 25266519 |
| Particular distribution of the GJB2/GJB6 gene mutations in Mexican population with hearing impairment. | Loeza-Becerra F | International journal of pediatric otorhinolaryngology | 2014 | PMID: 24774219 |
| GJB2-associated hearing loss undetected by hearing screening of newborns. | Minami SB | Gene | 2013 | PMID: 24013081 |
| Spectrum and frequency of GJB2 mutations in a cohort of 264 Portuguese nonsyndromic sensorineural hearing loss patients. | Matos TD | International journal of audiology | 2013 | PMID: 23668481 |
| Prevalence of DFNB1 mutations in Slovak patients with non-syndromic hearing loss. | Minárik G | International journal of pediatric otorhinolaryngology | 2012 | PMID: 22281373 |
| GJB2 allele variants and the associated audiologic features identified in Chinese patients with less severe idiopathic hearing loss. | Zhang J | Genetic testing and molecular biomarkers | 2011 | PMID: 21366436 |
| Analysis of the GJB2 and GJB6 genes in Italian patients with nonsyndromic hearing loss: frequencies, novel mutations, genotypes, and degree of hearing loss. | Primignani P | Genetic testing and molecular biomarkers | 2009 | PMID: 19371219 |
| Audiologic and temporal bone imaging findings in patients with sensorineural hearing loss and GJB2 mutations. | Lee KH | The Laryngoscope | 2009 | PMID: 19235794 |
| A new large deletion in the DFNB1 locus causes nonsyndromic hearing loss. | Feldmann D | European journal of medical genetics | 2009 | PMID: 19101659 |
| A novel M163L mutation in connexin 26 causing cell death and associated with autosomal dominant hearing loss. | Matos TD | Hearing research | 2008 | PMID: 18472371 |
| A novel hearing-loss-related mutation occurring in the GJB2 basal promoter. | Matos TD | Journal of medical genetics | 2007 | PMID: 17660464 |
| GJB2 mutations and degree of hearing loss: a multicenter study. | Snoeckx RL | American journal of human genetics | 2005 | PMID: 16380907 |
| Connexin 26 variants and auditory neuropathy/dys-synchrony among children in schools for the deaf. | Cheng X | American journal of medical genetics. Part A | 2005 | PMID: 16222667 |
| 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 |
| Effectiveness of sequencing connexin 26 (GJB2) in cases of familial or sporadic childhood deafness referred for molecular diagnostic testing. | Wu BL | Genetics in medicine : official journal of the American College of Medical Genetics | 2002 | PMID: 12172394 |
| Connexin 26 studies in patients with sensorineural hearing loss. | Kenna MA | Archives of otolaryngology--head & neck surgery | 2001 | PMID: 11556849 |
| Pattern of connexin 26 (GJB2) mutations causing sensorineural hearing impairment in Ghana. | Hamelmann C | Human mutation | 2001 | PMID: 11439000 |
| 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 |
| click to load more click to collapse | ||||
Text-mined citations for rs104894409 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 03, 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.