ClinVar Genomic variation as it relates to human health
NM_004004.6(GJB2):c.2T>C (p.Met1Thr)
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.2T>C (p.Met1Thr)
Variation ID: 371781 Accession: VCV000371781.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q12.11 13: 20189580 (GRCh38) [ NCBI UCSC ] 13: 20763719 (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 Jan 7, 2017 Apr 6, 2024 Mar 28, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004004.6(GJB2):c.2T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_004004.6:c.2T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003995.2:p.Met1Thr missense initiator codon variant NC_000013.11:g.20189580A>G NC_000013.10:g.20763719A>G NG_008358.1:g.8396T>C LRG_1350:g.8396T>C LRG_1350t1:c.2T>C LRG_1350p1:p.Met1Thr - Protein change
- M1T
- Other names
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- Canonical SPDI
- NC_000013.11:20189579:A: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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
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
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 | 617 |
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
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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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Likely pathogenic (1) |
criteria provided, single submitter
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Oct 11, 2016 | RCV000409687.8 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 11, 2016 | RCV000410366.8 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Nov 17, 2023 | RCV000991847.18 | |
Pathogenic (2) |
reviewed by expert panel
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Mar 28, 2024 | RCV001171533.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Nov 22, 2022 | RCV003418088.4 |
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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Pathogenic
(Mar 28, 2024)
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reviewed by expert panel
Method: curation
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Nonsyndromic genetic hearing loss
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Hearing Loss Variant Curation Expert Panel
Accession: SCV001334318.3
First in ClinVar: Jun 07, 2020 Last updated: Apr 06, 2024 |
Comment:
The c.2T>C (p.Met1Thr) variant in GJB2 may cause a truncated or absent protein by altering the start codon of the coding sequence and is predicted … (more)
The c.2T>C (p.Met1Thr) variant in GJB2 may cause a truncated or absent protein by altering the start codon of the coding sequence and is predicted to lead to the omission of a critical region of the protein. There have been multiple pathogenic variants observed in the region between this site and the next expected start codon (PVS1; ClinVar Variation IDs: 21387, 188758). There are also multiple pathogenic/likely pathogenic start-loss variants at this position which may indicate that this residue is critical to the function of the protein (ClinVar Variation IDs: 44729, 2070085, 550716, 551915). This variant has been observed in 0.0074% (8/107882) of the African population in the All of Us database (PM2_Supporting). It was identified in 1 patient with bilateral sensorineural hearing loss who also harbored an assumed trans pathogenic variant (0.5 PM3_Supporting points; Athena Diagnostics internal data, SCV001143666.1). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PVS1, PM2_Supporting, PM3_Supporting (VCEP specifications version 2; 10.18.2023). (less)
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Pathogenic
(Nov 09, 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: SCV001143666.2
First in ClinVar: Jan 19, 2020 Last updated: Sep 03, 2023 |
Comment:
The variant disrupts the natural start codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one … (more)
The variant disrupts the natural start codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity. (less)
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Likely pathogenic
(Aug 22, 2022)
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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: SCV000919428.3
First in ClinVar: Jun 02, 2019 Last updated: Sep 03, 2023 |
Comment:
Variant summary: GJB2 c.2T>C (p.Met1Thr) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded … (more)
Variant summary: GJB2 c.2T>C (p.Met1Thr) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Three of four 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 249204 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2T>C in individuals affected with Non-Syndromic Hearing Loss and no experimental evidence demonstrating its impact on protein function have been reported. This variant disrupts the start codon for protein translation (ATG becomes ACG) and the next start codon is 32 amino acids downstream. Variants affecting the same codon (M1V) and other codons within the N terminal 32 amino acids (such as L6P, Q7P, L10P, G12V, R32C, etc) have been reported in many affected individuals, suggesting the functional importance of this codon and the N terminal region of this protein (example: PMID: 29605365, PMID: 9482292). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as pathogenic(n=3)/likely pathogenic(n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Likely pathogenic
(Oct 11, 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:
unknown
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Counsyl
Accession: SCV000487741.3
First in ClinVar: Jan 07, 2017 Last updated: Sep 03, 2023 |
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Likely pathogenic
(Oct 11, 2016)
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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:
unknown
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Counsyl
Accession: SCV000487742.3
First in ClinVar: Jan 07, 2017 Last updated: Sep 03, 2023 |
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Pathogenic
(Jan 07, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001818526.4
First in ClinVar: Sep 08, 2021 Last updated: Sep 03, 2023 |
Comment:
Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); … (more)
Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Identified in one individual with a low grade glioma from a cohort of cancer patients as part of a large investigation of cancer predisposition variants (Huang et al., 2018); This variant is associated with the following publications: (PMID: 29625052) (less)
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Likely pathogenic
(Nov 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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GJB2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004116825.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The GJB2 c.2T>C variant is predicted to disrupt the translation initiation site (Start loss). To our knowledge, this variant has not been reported in a … (more)
The GJB2 c.2T>C variant is predicted to disrupt the translation initiation site (Start loss). To our knowledge, this variant has not been reported in a patient with hearing loss or deafness. However, two other variants that also result in start loss (p.Met1Ile, p.Met1Val) have been reported in patients with nonsyndromic hearing loss (Huang et al. 2018. PubMed ID: 29605365; Estivill et al. 1998. PubMed ID: 9482292). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-20763719-A-G). This variant is interpreted as likely pathogenic. (less)
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Pathogenic
(Nov 17, 2023)
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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: SCV001225573.6
First in ClinVar: Apr 15, 2020 Last updated: Feb 20, 2024 |
Comment:
This sequence change affects the initiator methionine of the GJB2 mRNA. The next in-frame methionine is located at codon 34. This variant is present in … (more)
This sequence change affects the initiator methionine of the GJB2 mRNA. The next in-frame methionine is located at codon 34. This variant is present in population databases (rs371086981, gnomAD 0.003%). Disruption of the initiator codon has been observed in individual(s) with autosomal recessive nonsyndromic deafness (PMID: 9482292, 29605365). ClinVar contains an entry for this variant (Variation ID: 371781). Studies have shown that disruption of the initiator codon alters GJB2 gene expression (PMID: 12189493). This variant disrupts a region of the GJB2 protein in which other variant(s) (p.Gly12Val) have been determined to be pathogenic (PMID: 10982180, 19371219, 24158611, 25288386). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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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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Pathogenic Germline Variants in 10,389 Adult Cancers. | Huang KL | Cell | 2018 | PMID: 29625052 |
Genetic mutations in non-syndromic deafness patients in Hainan Province have a different mutational spectrum compared to patients from Mainland China. | Huang B | International journal of pediatric otorhinolaryngology | 2018 | PMID: 29605365 |
GJB2 and GJB6 mutations are an infrequent cause of autosomal-recessive nonsyndromic hearing loss in residents of Mexico. | Hernández-Juárez AA | International journal of pediatric otorhinolaryngology | 2014 | PMID: 25288386 |
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 |
Asymmetric configurations and N-terminal rearrangements in connexin26 gap junction channels. | Oshima A | Journal of molecular biology | 2011 | PMID: 21094651 |
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 |
Human connexin26 (GJB2) deafness mutations affect the function of gap junction channels at different levels of protein expression. | Thönnissen E | Human genetics | 2002 | PMID: 12189493 |
Molecular basis of childhood deafness resulting from mutations in the GJB2 (connexin 26) gene. | Rabionet R | Human genetics | 2000 | PMID: 10982180 |
Connexin-26 mutations in sporadic and inherited sensorineural deafness. | Estivill X | Lancet (London, England) | 1998 | PMID: 9482292 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/ee804ee2-6db6-463d-b90d-51e2fd2374f2 | - | - | - | - |
Text-mined citations for rs371086981 ...
HelpRecord last updated Apr 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.