ClinVar Genomic variation as it relates to human health
NM_004004.6(GJB2):c.131G>A (p.Trp44Ter)
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.131G>A (p.Trp44Ter)
Variation ID: 188830 Accession: VCV000188830.28
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q12.11 13: 20189451 (GRCh38) [ NCBI UCSC ] 13: 20763590 (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 Mar 29, 2015 Feb 14, 2024 Oct 25, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004004.6:c.131G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003995.2:p.Trp44Ter nonsense NC_000013.11:g.20189451C>T NC_000013.10:g.20763590C>T NG_008358.1:g.8525G>A LRG_1350:g.8525G>A LRG_1350t1:c.131G>A LRG_1350p1:p.Trp44Ter - Protein change
- W44*
- Other names
- GJB2, TRP44TER (rs104894413)
- Canonical SPDI
- NC_000013.11:20189450:C:T
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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.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
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
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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
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 |
557 | 620 |
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/Likely pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Nov 12, 2020 | RCV000169176.23 | |
Pathogenic (1) |
criteria provided, single submitter
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May 18, 2017 | RCV000515211.10 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Oct 25, 2023 | RCV000517231.27 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 1, 2016 | RCV000624765.10 |
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
(Aug 08, 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:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000698229.1
First in ClinVar: Sep 26, 2017 Last updated: Sep 26, 2017 |
Comment:
Variant summary: The GJB2 c.131G>A (p.Trp44X) variant results in a premature termination codon, predicted to cause a truncated or absent GJB2 protein due to nonsense … (more)
Variant summary: The GJB2 c.131G>A (p.Trp44X) variant results in a premature termination codon, predicted to cause a truncated or absent GJB2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g., c.139G>T [p.Glu47X], c.167delT [p.Leu56fsX26], and c.169C>T [p.Gln57X]). One in silico tool predicts a damaging outcome for this variant. This variant was found in the large control database ExAC and in control cohorts from the literature at a frequency of 0.0000082 (1/121870 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). The variant has been identified in numerous patients reported in the literature in compound heterozygosity with known pathogenic GJB2 variants and as a homozygous allele (e.g., Carranza_CG_2015). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic and pathogenic. Taken together, this variant is classified as pathogenic. (less)
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Pathogenic
(Jul 08, 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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Athena Diagnostics
Accession: SCV000613505.2
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
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Pathogenic
(May 20, 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: SCV000227321.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 4
Sex: mixed
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Pathogenic
(Apr 04, 2019)
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criteria provided, single submitter
Method: clinical testing
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Deafness, autosomal recessive 1A
Affected status: unknown
Allele origin:
germline
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Knight Diagnostic Laboratories, Oregon Health and Sciences University
Accession: SCV001448943.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 1
Sex: male
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Pathogenic
(Sep 25, 2019)
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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:
unknown
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Baylor Genetics
Accession: SCV001523111.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
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Pathogenic
(Nov 12, 2020)
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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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Illumina Laboratory Services, Illumina
Accession: SCV001786660.1
First in ClinVar: Aug 14, 2021 Last updated: Aug 14, 2021 |
Comment:
The GJB2 c.131G>A (p.Trp44Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Trp44Ter variant has … (more)
The GJB2 c.131G>A (p.Trp44Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Trp44Ter variant has been reported in a homozygous state in six individuals with hearing loss and is noted to be a founder variant in the Guatemalan population (Carranza et al. 2016). The variant is also found in a compound heterozygous state with other predicted loss of function variants in at least two affected individuals (Tang et al. 2006). This variant is found at a frequency of in the 0.000174 in the Latino population of the Genome Aggregation Database. Based on the collective evidence and application of the ACMG criteria, the p.Trp44Ter variant is classified as pathogenic for autosomal recessive non-syndromic hearing loss. (less)
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Likely pathogenic
(Jun 12, 2014)
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criteria provided, single submitter
Method: literature only
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Deafness, autosomal recessive 1A
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000220409.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
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Pathogenic
(Nov 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV000741870.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Bilateral sensorineural hearing impairment (present) , Hyperactivity (present) , Downslanted palpebral fissures (present) , Protruding ear (present) , Few cafe-au-lait spots (present)
Sex: male
Ethnicity/Population group: Caucasian / Hispanic
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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: yes
Allele origin:
germline
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Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000599731.1
First in ClinVar: Sep 19, 2017 Last updated: Sep 19, 2017 |
Number of individuals with the variant: 1
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Pathogenic
(May 18, 2017)
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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: SCV000611267.1
First in ClinVar: Nov 11, 2017 Last updated: Nov 11, 2017 |
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Pathogenic
(Aug 29, 2019)
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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: SCV000885519.2
First in ClinVar: Dec 15, 2018 Last updated: Jan 26, 2021 |
Comment:
The GJB2 c.131G>A; p.Trp44Ter variant (rs104894413) is reported in the literature in multiple individuals affected with nonsyndromic sensorineural hearing loss, both in the homozygous state … (more)
The GJB2 c.131G>A; p.Trp44Ter variant (rs104894413) is reported in the literature in multiple individuals affected with nonsyndromic sensorineural hearing loss, both in the homozygous state and in individuals with a second pathogenic variant (Tang 2006, Carranza 2016, Snoeckx 2005, Putcha 2007, Lipan 2011, Roux 2004). In a large North American cohort, the p.Trp44Ter variant was determined as the sixth most common variant in individuals with African descent (Putcha 2007), and it was reported as the most common variant observed in unrelated deaf families from Guatemala, consistent with a founder effect in the Mayan population (Carranza 2016). This variant is found on only six chromosomes (6/250896 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on these observations, the p.Trp44Ter variant is considered to be pathogenic. References: Carranza et al. A Mayan founder mutation is a common cause of deafness in Guatemala. Clin Genet. 2016 Apr;89(4):461-465. Lipan et al. Clinical comparison of hearing-impaired patients with DFNB1 against heterozygote carriers of connexin 26 mutations. Laryngoscope. 2011 Apr;121(4):811-4. Putcha 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. Roux et al. Molecular epidemiology of DFNB1 deafness in France. BMC Med Genet. 2004 Mar 6;5:5. Snoeckx et al. GJB2 mutations and degree of hearing loss: a multicenter study. Am J Hum Genet. 2005 Dec;77(6):945-57. Tang et al. DNA sequence analysis of GJB2, encoding connexin 26: observations from a population of hearing impaired cases and variable carrier rates, complex genotypes, and ethnic stratification of alleles among controls. Am J Med Genet A. 2006 Nov 15;140(22):2401-15. (less)
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Pathogenic
(Dec 07, 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: SCV000890303.3
First in ClinVar: Mar 19, 2019 Last updated: Mar 04, 2023 |
Comment:
Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 183 amino acids are lost, and other loss-of-function variants have been … (more)
Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 183 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); A different nucleotide change (c.132 G>A) leading to the same nonsense variant has been reported as pathogenic in the published literature and at GeneDx in association with autosomal recessive nonsyndromic hearing loss (Green et al., 1999; Roux et al., 2004; Angeli et al., 2008; Mirna et al., 2015); This variant is associated with the following publications: (PMID: 11102979, 21131880, 10376574, 17041943, 26553399, 16380907, 12325027, 24774219, 21287563, 26582918, 26346709, 15070423, 18758381, 24077912, 27535533) (less)
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Pathogenic
(Oct 25, 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: SCV001589924.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Trp44*) 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.Trp44*) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 183 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs104894413, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with autosomal recessive GJB2-related conditions (PMID: 26346709, 31620164). ClinVar contains an entry for this variant (Variation ID: 188830). This variant disrupts a region of the GJB2 protein in which other variant(s) (p.Trp172*) have been determined to be pathogenic (PMID: 23668481, 26399936, 29773520). 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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Pathogenic
(Oct 16, 2016)
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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: SCV000280012.3
First in ClinVar: May 29, 2016 Last updated: Aug 22, 2016 |
Comment on evidence:
In 6 Guatemalan probands with autosomal recessive deafness-1A (DFNB1A; 220290), Carranza et al. (2016) identified a homozygous c.131G-A transition (rs104894413) in the GJB2 gene, resulting … (more)
In 6 Guatemalan probands with autosomal recessive deafness-1A (DFNB1A; 220290), Carranza et al. (2016) identified a homozygous c.131G-A transition (rs104894413) in the GJB2 gene, resulting in a trp44-to-ter (W44X) substitution. Two additional probands with deafness were compound heterozygous for the W44X mutation and another pathogenic mutation. The patients were from a cohort of 133 Guatemalan families with hearing loss who underwent sequencing of the GJB2 gene. The W44X mutation was the most common GJB2 pathogenic variant identified, accounting for 21 of 266 alleles, and 62% of the mutant GJB2 alleles identified. Haplotype analysis indicated a founder effect in this population, and ancestry analysis of individuals with this pathogenic variant showed a close match with Mayans. The W44X mutation always occurred with a benign c.79G-A variant (V27I) in the GJB2 gene. Functional studies and studies of patient cells were not performed. (less)
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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: SCV001453354.1
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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GJB2 and GJB6 Mutations in Non-Syndromic Childhood Hearing Impairment in Ghana. | Adadey SM | Frontiers in genetics | 2019 | PMID: 31620164 |
Frequency of GJB2 mutations in patients with nonsyndromic hearing loss from an ethnically characterized Brazilian population. | Felix F | Brazilian journal of otorhinolaryngology | 2019 | PMID: 29773520 |
A Mayan founder mutation is a common cause of deafness in Guatemala. | Carranza C | Clinical genetics | 2016 | PMID: 26346709 |
Screening of genetic alterations related to non-syndromic hearing loss using MassARRAY iPLEX® technology. | Svidnicki MC | BMC medical genetics | 2015 | PMID: 26399936 |
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 |
Clinical comparison of hearing-impaired patients with DFNB1 against heterozygote carriers of connexin 26 mutations. | Lipan M | The Laryngoscope | 2011 | PMID: 21287563 |
Comprehensive diagnostic battery for evaluating sensorineural hearing loss in children. | Lin JW | Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology | 2011 | PMID: 21131880 |
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 |
DNA sequence analysis of GJB2, encoding connexin 26: observations from a population of hearing impaired cases and variable carrier rates, complex genotypes, and ethnic stratification of alleles among controls. | Tang HY | American journal of medical genetics. Part A | 2006 | PMID: 17041943 |
GJB2 mutations and degree of hearing loss: a multicenter study. | Snoeckx RL | American journal of human genetics | 2005 | PMID: 16380907 |
Molecular epidemiology of DFNB1 deafness in France. | Roux AF | BMC medical genetics | 2004 | PMID: 15070423 |
Genetic testing for hereditary hearing loss: connexin 26 (GJB2) allele variants and two novel deafness-causing mutations (R32C and 645-648delTAGA). | Prasad S | Human mutation | 2000 | PMID: 11102979 |
Carrier rates in the midwestern United States for GJB2 mutations causing inherited deafness. | Green GE | JAMA | 1999 | PMID: 10376574 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GJB2 | - | - | - | - |
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Text-mined citations for rs104894413 ...
HelpRecord last updated May 19, 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.