ClinVar Genomic variation as it relates to human health
NM_004004.6(GJB2):c.257C>G (p.Thr86Arg)
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.
Pathogenic(4); Likely pathogenic(1); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_004004.6(GJB2):c.257C>G (p.Thr86Arg)
Variation ID: 631697 Accession: VCV000631697.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q12.11 13: 20189325 (GRCh38) [ NCBI UCSC ] 13: 20763464 (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 May 27, 2019 Feb 14, 2024 Jan 7, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004004.6:c.257C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003995.2:p.Thr86Arg missense NC_000013.11:g.20189325G>C NC_000013.10:g.20763464G>C NG_008358.1:g.8651C>G LRG_1350:g.8651C>G LRG_1350t1:c.257C>G LRG_1350p1:p.Thr86Arg - Protein change
- T86R
- Other names
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- Canonical SPDI
- NC_000013.11:20189324:G:C
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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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- Links
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 | 617 |
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
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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 (1) |
criteria provided, single submitter
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Aug 15, 2018 | RCV000778387.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 19, 2017 | RCV001113900.4 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jan 3, 2022 | RCV001113901.6 | |
Pathogenic (1) |
no assertion criteria provided
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Oct 2, 2020 | RCV001374648.1 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 7, 2024 | RCV001784383.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 20, 2023 | RCV003317365.1 |
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
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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
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
(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: SCV000914615.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
Across a selection of the available literature, the GJB2 c.257C>G (p.Thr86Arg) missense variant, which has been found mainly in the East Asian population, was identified … (more)
Across a selection of the available literature, the GJB2 c.257C>G (p.Thr86Arg) missense variant, which has been found mainly in the East Asian population, was identified in a homozygous state in at least one individual with autosomal recessive nonsyndromic hearing loss and in a compound heterozygous state in at least four unrelated individuals, also with autosomal recessive nonsyndromic hearing loss (Ohtsuka et al. 2003; Choi et al. 2009; Shi et al. 2016; Sakuma et al. 2016; Zhang et al. 2016). Huang et al. (2013) further identified one patient with profound bilateral sensorineural hearing loss and enlarged vestibular aqueduct with double biallelic variants in the GJB2 and SLC26A4 genes; the patient was compound heterozygous for the p.Thr86Arg variant and a pathogenic frameshift variant common in the East Asian population. The p.Thr86Arg variant was absent from 247 controls but is reported at a frequency of 0.00006 in the East Asian population of the Genome Aggregation Database, based on one allele in a region of good sequence coverage so the variant is presumed to be rare. HEK293 cells transfected with the variant protein demonstrated that the p.Thr86Arg variant led to defective intercellular trafficking and oligomerization of the protein (Choi et al. 2009). Co-transfection with the wild type channel demonstrated that the p.Thr86Arg variant did not affect ionic transfer and biochemical coupling, consistent with the recessive nature of the variant. Based on the collective evidence, the p.Thr86Arg 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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Uncertain significance
(Sep 19, 2017)
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criteria provided, single submitter
Method: clinical testing
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Ichthyosis, hystrix-like, with hearing loss
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001271711.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Sep 19, 2017)
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criteria provided, single submitter
Method: clinical testing
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Autosomal dominant nonsyndromic hearing loss 3A
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001271712.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Likely pathogenic
(Jan 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Autosomal dominant nonsyndromic hearing loss 3A
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002058814.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported to be associated with GJB2 related disorder (PMID:12560944, PS1_P). The variant has … (more)
Same nucleotide change resulting in same amino acid change has been previously reported to be associated with GJB2 related disorder (PMID:12560944, PS1_P). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PM3_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.969, 3CNET: 0.989, PP3_P). A missense variant is a common mechanism associated with Deafness (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Hearing impairment (present)
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Pathogenic
(Jun 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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Nonsyndromic genetic hearing loss
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004020946.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
Variant summary: GJB2 c.257C>G (p.Thr86Arg) results in a non-conservative amino acid change located in the Connexin, N-terminal domain (IPR013092) of the encoded protein sequence. Five … (more)
Variant summary: GJB2 c.257C>G (p.Thr86Arg) results in a non-conservative amino acid change located in the Connexin, N-terminal domain (IPR013092) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251278 control chromosomes (gnomAD). c.257C>G has been reported in the literature as a biallelic genotype in multiple individuals affected with Hearing Loss (e.g. Ohtsuka_2003, Choi_2009, Huang_2013, Xu_2014). These data indicate that the variant is very likely to be associated with disease. When expressed alone in HEK293 cells, the variant protein failed to form gap junctions and had deficient hemichannel opening (Choi_2009). This deficiency was rescued when the variant was co-expressed with WT-GJB2, supporting the recessive nature of this specific variant. The following publications have been ascertained in the context of this evaluation (PMID: 19384972, 23266159, 12560944, 24941117). Six ClinVar submitters have assessed this variant since 2014: one classified the variant as uncertain significance, one as likely pathogenic, and four as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Sep 28, 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: SCV002024272.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 07, 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: SCV002222811.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 86 of the GJB2 protein (p.Thr86Arg). … (more)
This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 86 of the GJB2 protein (p.Thr86Arg). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individuals with autosomal recessive deafness (PMID: 19384972, 26763877, 30896630, 31160754). ClinVar contains an entry for this variant (Variation ID: 631697). 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%. Experimental studies have shown that this missense change affects GJB2 function (PMID: 19384972). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 02, 2020)
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no assertion criteria provided
Method: clinical testing
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nonsyndromic sensorineural hearing loss
Affected status: yes
Allele origin:
germline
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Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals
Accession: SCV001571570.1
First in ClinVar: Apr 22, 2021 Last updated: Apr 22, 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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GJB2-Related Autosomal Recessive Nonsyndromic Hearing Loss. | Adam MP | - | 2023 | PMID: 20301449 |
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 |
Panel-based NGS reveals disease-causing mutations in hearing loss patients using BGISEQ-500 platform. | Sun Y | Medicine | 2019 | PMID: 30896630 |
Prevalence of GJB2 gene mutation in 330 cochlear implant patients in the Jiangsu province. | Shi L | The Journal of laryngology and otology | 2016 | PMID: 27534436 |
Mutation Analysis of the Common Deafness Genes in Patients with Nonsyndromic Hearing Loss in Linyi by SNPscan Assay. | Zhang F | BioMed research international | 2016 | PMID: 27247933 |
An effective screening strategy for deafness in combination with a next-generation sequencing platform: a consecutive analysis. | Sakuma N | Journal of human genetics | 2016 | PMID: 26763877 |
Analysis of common deafness gene mutations in deaf people from unique ethnic groups in Gansu Province, China. | Xu BC | Acta oto-laryngologica | 2014 | PMID: 24941117 |
Sensorineural hearing loss caused by mutations in two alleles of both GJB2 and SLC26A4 genes. | Huang S | International journal of pediatric otorhinolaryngology | 2013 | PMID: 23266159 |
Different functional consequences of two missense mutations in the GJB2 gene associated with non-syndromic hearing loss. | Choi SY | Human mutation | 2009 | PMID: 19384972 |
GJB2 deafness gene shows a specific spectrum of mutations in Japan, including a frequent founder mutation. | Ohtsuka A | Human genetics | 2003 | PMID: 12560944 |
Text-mined citations for rs1291519904 ...
HelpRecord last updated Mar 17, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.