ClinVar Genomic variation as it relates to human health
NM_004004.6(GJB2):c.250G>C (p.Val84Leu)
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.250G>C (p.Val84Leu)
Variation ID: 17032 Accession: VCV000017032.28
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q12.11 13: 20189332 (GRCh38) [ NCBI UCSC ] 13: 20763471 (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 Nov 23, 2014 Feb 14, 2024 Dec 14, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004004.6:c.250G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003995.2:p.Val84Leu missense NC_000013.11:g.20189332C>G NC_000013.10:g.20763471C>G NG_008358.1:g.8644G>C LRG_1350:g.8644G>C LRG_1350t1:c.250G>C LRG_1350p1:p.Val84Leu P29033:p.Val84Leu - Protein change
- V84L
- Other names
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- Canonical SPDI
- NC_000013.11:20189331:C: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.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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
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. |
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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
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 (6) |
criteria provided, multiple submitters, no conflicts
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Jun 2, 2023 | RCV000018560.41 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 8, 2013 | RCV000146012.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 22, 2017 | RCV000211770.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 21, 2020 | RCV001257042.2 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Dec 14, 2023 | RCV001041795.11 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV003335046.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 8, 2021 | RCV002504805.1 |
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
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
(Oct 08, 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: SCV002808981.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jun 02, 2023)
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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:
germline
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Integrating Genomics into Medicine, Frazer Institute, University Of Queensland
Accession: SCV003935272.1
First in ClinVar: Jul 01, 2023 Last updated: Jul 01, 2023 |
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Pathogenic
(Jun 15, 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: SCV001770240.2
First in ClinVar: Aug 07, 2021 Last updated: Jul 22, 2023 |
Comment:
Published functional studies demonstrate a damaging effect on biochemical permeability, while ionic coupling is intact (Zhang et al., 2005); In silico analysis supports that this … (more)
Published functional studies demonstrate a damaging effect on biochemical permeability, while ionic coupling is intact (Zhang et al., 2005); 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: 17426645, 24158611, 23555729, 15365987, 25087612, 25388846, 15592461, 16380907, 14985372, 12562518, 12505163, 20441744, 16217030, 9529365, 17666888, 12189487, 11556849, 31160754, 33096615, 31589614, 34308104, 31331740) (less)
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Pathogenic
(Feb 08, 2013)
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criteria provided, single submitter
Method: clinical testing
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Hearing impairment
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000193163.1
First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014 |
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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: SCV000599740.1
First in ClinVar: Sep 19, 2017 Last updated: Sep 19, 2017 |
Number of individuals with the variant: 1
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Pathogenic
(Feb 22, 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: SCV000698239.1
First in ClinVar: Sep 19, 2017 Last updated: Sep 19, 2017 |
Comment:
Variant summary: The GJB2 c.250G>C (p.Val84Leu) variant involves the alteration of a conserved nucleotide and is predicted to be damaging by 3/4 in silico tools … (more)
Variant summary: The GJB2 c.250G>C (p.Val84Leu) variant involves the alteration of a conserved nucleotide and is predicted to be damaging by 3/4 in silico tools (SNPs&GO not captured due to low reliability index). The Val84 is proposed to be at the membrane-spanning segments M2/M3 helix interface of the GJB2 protein (Ambrosi_2010). This variant was found in 8/121696 control chromosomes from ExAC at a frequency of 0.0000657, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). This variant is widely reported as a pathogenic variant in literature and is found in ARNSHL patients in homozygous as well as in compound heterozygous state with other known pathogenic variants, including evidence of cosegregation with disease (Kelley_1998, Azaiez_2004, Snoeckx_2005, Zoll_2002, Dalamon_2013, Dahl_2013). Multiple functional studies show that although the V84L mutant channels are able to make gap junctions in mammalian and insect cells, stable in detergent solution and able to allow passage of simple ions (such as LY), they do not allow permeability for molecules larger than simple ions (such as propidium iodide) and reduce permeability to the Ca2+-mobilizing messenger inositol 1,4,5-trisphosphate (Bruzzone_2003, Wang_2003, Beltramello_2005, Zhang_2005, Ambrosi_2010). In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Another missense variant at this residue p.V84M has been classified as pathogenic by our lab and others in ClinVar. Taken together, this variant is classified as Pathogenic. (less)
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Pathogenic
(Jun 22, 2017)
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criteria provided, single submitter
Method: clinical testing
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Rare genetic deafness
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000061492.5
First in ClinVar: May 03, 2013 Last updated: Apr 09, 2018 |
Comment:
The p.Val84Leu variant in GJB2 has been reported in 7 individuals with hearing l oss, 6 of whom were compound heterozygous for a second pathogenic … (more)
The p.Val84Leu variant in GJB2 has been reported in 7 individuals with hearing l oss, 6 of whom were compound heterozygous for a second pathogenic variant and 1 of whom was homozygous for the variant, and segregated in 3 affected siblings wi th hearing loss (Cryns 2004, Kelley 1998, Kenna 2001, LMM Unpublished data). Thi s variant was identified in 4/33580 Latino chromosomes; however, this frequency is low enough to be consistent with a recessive carrier frequency. Functional st udies indicate that the Val84Leu variant compromises connexin 26 protein functio n (Beltramello 2005). In summary, this variant meets criteria to be classified a s pathogenic for autosomal recessive hearing loss based on the previously report ed individuals, segregation data, and low frequency in the general population. (less)
Number of individuals with the variant: 7
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Pathogenic
(Aug 21, 2020)
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criteria provided, single submitter
Method: clinical testing
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Nonsyndromic hearing loss and deafness
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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INGEBI, INGEBI / CONICET
Accession: SCV001433547.1
First in ClinVar: Sep 27, 2020 Last updated: Sep 27, 2020 |
Comment:
Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the c.250G>C, p.Val84Leu has a filtering allele frequency of 0.00395% in Latino population from … (more)
Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the c.250G>C, p.Val84Leu has a filtering allele frequency of 0.00395% in Latino population from Genome Aggregation Database v2.1.1 (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/) meeting PM2 criteria. Computational analysis predicted a pathogenic effect of the variant to the protein (REVELscore=0.947) applying to PP3 rule. This variant was identified in trans with at least 5 known pathogenic variants meeting PM3_VeryStrong criteria (PMID: 24158611, 95239365, 11556849,12172394, 12189487,12497637, 14985372, 15365987, 17041943). The p.Val84Leu change in trans with a pathogenic variant segregated in two affected siblings in a family case. (PP1_Supporting; PMID: 95239365). Dye transfer and electrical coupling assays demonstrated that the variant do not impact the protein function (PMID: 12505163, 12562518, 16217030). However, some assays showed a reduce permeability to IP3 and intracellular exchange of large molecules (PMID: 12505163, 16217030), and therefore this evidence was not counted. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic hearing loss (PM2, PP3, PM3_VeryStrong and PP1_Supporting). (less)
Number of individuals with the variant: 1
Clinical Features:
Prelingual moderate bilaterial hearing loss (present)
Family history: no
Sex: female
Ethnicity/Population group: Caucasian
Geographic origin: Argentina
Tissue: blood
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Pathogenic
(May 26, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics Inc
Accession: SCV001476374.2
First in ClinVar: Jan 26, 2021 Last updated: Sep 19, 2021 |
Comment:
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). At least one other missense variant at this codon is considered … (more)
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. This variant appears to segregate with disease in at least one family, however, the available information does not rule out segregation due to chance. Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies show this variant results in impaired permeability to larger molecules, such as inositol 1,4,5-trisphosphate (PMID: 15592461, 16217030). 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. Computational tools predict that this variant is damaging. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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GJB2-related disorders
Affected status: yes
Allele origin:
germline
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Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV004046406.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
This variant has been previously reported as a compound heterozygous or homozygous variant in individuals with congenital hearing impairment (PMID: 16380907, 26346709, 24013081, 19235794, 11556849, … (more)
This variant has been previously reported as a compound heterozygous or homozygous variant in individuals with congenital hearing impairment (PMID: 16380907, 26346709, 24013081, 19235794, 11556849, 12172394, 12189487, 12497637, 15365987). Functional studies have shown that this missense change affects biochemical permeability and intercellular transport of large molecules (PMID: 12505163, 12562518, 15592461, 20441744, 16217030). The c.250G>C (p.Val84Leu) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.004% (9/251338) and is absent in the homozygous state, thus is presumed to be rare. In silico analyses predict a deleterious effect of the c.250G>C (p.Val84Leu) variant on protein function. Based on the available evidence, the c.250G>C (p.Val84Leu) variant is classified as Pathogenic. (less)
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Pathogenic
(Dec 14, 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: SCV001205435.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 84 of the GJB2 protein (p.Val84Leu). … (more)
This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 84 of the GJB2 protein (p.Val84Leu). This variant is present in population databases (rs104894409, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive deafness (PMID: 11556849, 12172394, 16380907, 19235794, 24013081, 26346709). ClinVar contains an entry for this variant (Variation ID: 17032). 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: 12505163, 12562518, 15592461, 16217030, 20441744). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 01, 2005)
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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: SCV000038842.6
First in ClinVar: Apr 04, 2013 Last updated: May 12, 2020 |
Comment on evidence:
Kenna et al. (2001) identified a homozygous val84-to-leu (V84L) mutation in the GJB2 gene in a 4-year-old patient with autosomal recessive profound sensorineural hearing loss … (more)
Kenna et al. (2001) identified a homozygous val84-to-leu (V84L) mutation in the GJB2 gene in a 4-year-old patient with autosomal recessive profound sensorineural hearing loss (DFNB1A; 220290). Beltramello et al. (2005) found that CX26 carrying the V84L mutation sorted to the plasma membrane normally and formed gap junctions that were morphologically and electrically indistinguishable from those of control CX26. However, the mutation markedly reduced the permeability of CX26 gap junction channels to inositol 1,4,5-trisphosphate (Ins(1,4,5)P3), resulting in blockade of the Ins(1,4,5)P3-induced inward calcium current in neighboring cells. Beltramello et al. (2005) concluded that reduced Ins(1,4,5)P3 permeability impairs the propagation of calcium waves in cochlear-supporting cells. (less)
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Pathogenic
(Dec 18, 2019)
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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: SCV002086057.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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Pathogenic
(Nov 13, 2017)
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no assertion criteria provided
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: SCV001132401.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
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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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- | - | - | - | PMID: 10049954 |
- | - | - | - | PMID: 11556849 |
- | - | - | - | PMID: 12172394 |
- | - | - | - | PMID: 12189487 |
- | - | - | - | PMID: 12505163 |
- | - | - | - | PMID: 12562518 |
- | - | - | - | PMID: 14985372 |
- | - | - | - | PMID: 15365987 |
- | - | - | - | PMID: 15592461 |
- | - | - | - | PMID: 16217030 |
- | - | - | - | PMID: 16380907 |
- | - | - | - | PMID: 16849369 |
- | - | - | - | PMID: 17041943 |
- | - | - | - | PMID: 17426645 |
- | - | - | - | PMID: 17666888 |
- | - | - | - | PMID: 19235794 |
- | - | - | - | PMID: 20083784 |
- | - | - | - | PMID: 20441744 |
- | - | - | - | PMID: 22925408 |
- | - | - | - | PMID: 23555729 |
- | - | - | - | PMID: 24013081 |
- | - | - | - | PMID: 24158611 |
- | - | - | - | PMID: 25388846 |
- | - | - | - | PMID: 26188157 |
- | - | - | - | PMID: 26346709 |
- | - | - | - | PMID: 95239365 |
- | - | - | - | PMID: 9529365 |
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Text-mined citations for rs104894409 ...
HelpRecord last updated Feb 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.