ACMG classification criteria: PS3 supporting, PM4 moderate, BS1 strong
ClinVar Genomic variation as it relates to human health
NM_024009.3(GJB3):c.196_198del (p.Asp66del)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(8)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Conflicting classifications of pathogenicity
Pathogenic(1); Uncertain significance(6)
Pathogenic(1); Uncertain significance(6)
8
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_024009.3(GJB3):c.196_198del (p.Asp66del)
Variation ID: 6490 Accession: VCV000006490.45
- Type and length
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Deletion, 3 bp
- Location
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Cytogenetic: 1p34.3 1: 34784956-34784958 (GRCh38) [ NCBI UCSC ] 1: 35250557-35250559 (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 Jul 5, 2015 Oct 20, 2024 Jun 10, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_024009.3:c.196_198del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_076872.1:p.Asp66del inframe deletion NM_001005752.2:c.196_198del NP_001005752.1:p.Asp66del inframe deletion NM_024009.2:c.196_198delGAC NC_000001.11:g.34784958_34784960del NC_000001.10:g.35250559_35250561del NG_008309.1:g.8770_8772del - Protein change
- D66del
- Other names
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GJB3, 3-BP DEL, ASP66DEL
- Canonical SPDI
- NC_000001.11:34784955:ACGAC:AC
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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.
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- Links
- Comment on variant
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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| GJB3 | - | - |
GRCh38 GRCh37 |
206 | 218 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (1) |
no assertion criteria provided
|
Apr 15, 2001 | RCV000006863.6 | |
| Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
|
Jun 10, 2024 | RCV000345579.38 | |
| Uncertain significance (1) |
criteria provided, single submitter
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Jun 23, 2021 | RCV002243625.3 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Nov 20, 2022 | RCV002468963.2 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Mar 22, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000339768.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Number of individuals with the variant: 1
Sex: mixed
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Uncertain significance
(Jun 23, 2021)
|
criteria provided, single submitter
Method: clinical testing
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Hearing impairment
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002512635.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Comment:
ACMG classification criteria: PS3 supporting, PM4 moderate, BS1 strong
Geographic origin: Brazil
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Uncertain significance
(Nov 20, 2022)
|
criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002766454.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Variant summary: GJB3 c.196_198delGAC (p.Asp66del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele … (more)
Variant summary: GJB3 c.196_198delGAC (p.Asp66del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 0.00014 in 251390 control chromosomes. This frequency does not allow conclusions about variant significance. c.196_198delGAC has been reported in the literature as a dominant mutation in at-least one family with sensorineural hearing loss and peripheral neuropathy (5 genotyped affected transmissions) where it showed both non-segregation (one reference allele transmission to a genotyped affected) and variable penetrance (an unaffected individual with the variant) (example, Lopez-Bigas_2001).These data indicate that the variant may be associated with disease although the authors suggest that other genetic modifiers or environmental factors could contribute to the overall phenotypic spectrum of manifesations. At least two publications report experimental evidence evaluating an impact on protein function evaluating defective channel formation by localization studies and dye transfer experiments, however, do not allow convincing conclusions about the variant effect (example, Di_2002, Tattersall_2009). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=5; Pathogenic, n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. (less)
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Uncertain significance
(Jan 01, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002225560.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This variant, c.196_198del, results in the deletion of 1 amino acid(s) of the GJB3 protein (p.Asp66del), but otherwise preserves the integrity of the reading frame. … (more)
This variant, c.196_198del, results in the deletion of 1 amino acid(s) of the GJB3 protein (p.Asp66del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs777106179, gnomAD 0.04%). This variant has been observed in individual(s) with hearing impairment and/or neuropathy (PMID: 11309368, 35580552). ClinVar contains an entry for this variant (Variation ID: 6490). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects GJB3 function (PMID: 12165562). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Jun 10, 2024)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001772469.3
First in ClinVar: Aug 07, 2021 Last updated: Sep 29, 2024 |
Comment:
In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Published in vitro expression studies … (more)
In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Published in vitro expression studies suggest a damaging effect; a portion of the mutant protein does not reach the cell membrane suggestive of an intracellular trafficking defect and cells shows altered gap junction function, while there was no evidence for an increased rate of cell death in contrast to GJB3 variants associated with skin disorders (PMID: 12165562, 19755382); This variant is associated with the following publications: (PMID: 19755382, 11179004, 12165562, 11758118, 12823303, 29044474, 19197336, 35580552, 36515421, 36147510, 11309368) (less)
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Uncertain significance
(Mar 14, 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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Athena Diagnostics
Accession: SCV001144060.1
First in ClinVar: Jan 19, 2020 Last updated: Jan 19, 2020 |
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Pathogenic
(Jan 01, 2020)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001147224.27
First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 3
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Pathogenic
(Apr 15, 2001)
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no assertion criteria provided
Method: literature only
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DEAFNESS, AUTOSOMAL DOMINANT, WITH PERIPHERAL NEUROPATHY
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000027059.4
First in ClinVar: Apr 04, 2013 Last updated: Jun 02, 2024 |
Comment on evidence:
In affected members of a 4-generation Spanish family with autosomal deafness with peripheral neuropathy (DFNA2B; 612644), Lopez-Bigas et al. (2001) reported a 3-bp deletion in … (more)
In affected members of a 4-generation Spanish family with autosomal deafness with peripheral neuropathy (DFNA2B; 612644), Lopez-Bigas et al. (2001) reported a 3-bp deletion in the GJB3 gene, resulting in an asp deletion at codon 66. Nerve conduction studies revealed a markedly decreased amplitude with normal velocity, and sural nerve biopsy of 1 affected family member revealed a demyelination/remyelination appearance. In situ studies in mice demonstrated expression of Gjb3 in the cochlea and auditory nerve, and in the sciatic nerve similar to the expression pattern of Gjb1 (connexin-32; 304040). (less)
|
Comment:
Comment:
Variant summary: GJB3 c.196_198delGAC (p.Asp66del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 0.00014 in 251390 control chromosomes. This frequency does not allow conclusions about variant significance. c.196_198delGAC has been reported in the literature as a dominant mutation in at-least one family with sensorineural hearing loss and peripheral neuropathy (5 genotyped affected transmissions) where it showed both non-segregation (one reference allele transmission to a genotyped affected) and variable penetrance (an unaffected individual with the variant) (example, Lopez-Bigas_2001).These data indicate that the variant may be associated with disease although the authors suggest that other genetic modifiers or environmental factors could contribute to the overall phenotypic spectrum of manifesations. At least two publications report experimental evidence evaluating an impact on protein function evaluating defective channel formation by localization studies and dye transfer experiments, however, do not allow convincing conclusions about the variant effect (example, Di_2002, Tattersall_2009). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=5; Pathogenic, n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Comment:
This variant, c.196_198del, results in the deletion of 1 amino acid(s) of the GJB3 protein (p.Asp66del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs777106179, gnomAD 0.04%). This variant has been observed in individual(s) with hearing impairment and/or neuropathy (PMID: 11309368, 35580552). ClinVar contains an entry for this variant (Variation ID: 6490). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects GJB3 function (PMID: 12165562). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Published in vitro expression studies suggest a damaging effect; a portion of the mutant protein does not reach the cell membrane suggestive of an intracellular trafficking defect and cells shows altered gap junction function, while there was no evidence for an increased rate of cell death in contrast to GJB3 variants associated with skin disorders (PMID: 12165562, 19755382); This variant is associated with the following publications: (PMID: 19755382, 11179004, 12165562, 11758118, 12823303, 29044474, 19197336, 35580552, 36515421, 36147510, 11309368)
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
ACMG classification criteria: PS3 supporting, PM4 moderate, BS1 strong
Comment:
Variant summary: GJB3 c.196_198delGAC (p.Asp66del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 0.00014 in 251390 control chromosomes. This frequency does not allow conclusions about variant significance. c.196_198delGAC has been reported in the literature as a dominant mutation in at-least one family with sensorineural hearing loss and peripheral neuropathy (5 genotyped affected transmissions) where it showed both non-segregation (one reference allele transmission to a genotyped affected) and variable penetrance (an unaffected individual with the variant) (example, Lopez-Bigas_2001).These data indicate that the variant may be associated with disease although the authors suggest that other genetic modifiers or environmental factors could contribute to the overall phenotypic spectrum of manifesations. At least two publications report experimental evidence evaluating an impact on protein function evaluating defective channel formation by localization studies and dye transfer experiments, however, do not allow convincing conclusions about the variant effect (example, Di_2002, Tattersall_2009). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=5; Pathogenic, n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Comment:
This variant, c.196_198del, results in the deletion of 1 amino acid(s) of the GJB3 protein (p.Asp66del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs777106179, gnomAD 0.04%). This variant has been observed in individual(s) with hearing impairment and/or neuropathy (PMID: 11309368, 35580552). ClinVar contains an entry for this variant (Variation ID: 6490). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects GJB3 function (PMID: 12165562). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Published in vitro expression studies suggest a damaging effect; a portion of the mutant protein does not reach the cell membrane suggestive of an intracellular trafficking defect and cells shows altered gap junction function, while there was no evidence for an increased rate of cell death in contrast to GJB3 variants associated with skin disorders (PMID: 12165562, 19755382); This variant is associated with the following publications: (PMID: 19755382, 11179004, 12165562, 11758118, 12823303, 29044474, 19197336, 35580552, 36515421, 36147510, 11309368)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Whole-Exome Sequencing Targeting a Gene Panel for Sensorineural Hearing Loss: The First Portuguese Cohort Study. | Reis CS | Cytogenetic and genome research | 2022 | PMID: 35580552 |
| Exome Sequencing Identifies a Novel Nonsense Mutation of MYO6 as the Cause of Deafness in a Brazilian Family. | Sampaio-Silva J | Annals of human genetics | 2018 | PMID: 29044474 |
| Mechanism of a novel missense mutation, p.V174M, of the human connexin31 (GJB3) in causing nonsyndromic hearing loss. | Li TC | Biochemistry and cell biology = Biochimie et biologie cellulaire | 2014 | PMID: 24913888 |
| A missense mutation in the GJB3 gene responsible for erythrokeratodermia variabilis in a Chinese family. | Wang W | Clinical and experimental dermatology | 2012 | PMID: 22681493 |
| Trafficking abnormality and ER stress underlie functional deficiency of hearing impairment-associated connexin-31 mutants. | Xia K | Protein & cell | 2010 | PMID: 21204020 |
| EKV mutant connexin 31 associated cell death is mediated by ER stress. | Tattersall D | Human molecular genetics | 2009 | PMID: 19755382 |
| The genetic bases for non-syndromic hearing loss among Chinese. | Ouyang XM | Journal of human genetics | 2009 | PMID: 19197336 |
| Digenic inheritance of non-syndromic deafness caused by mutations at the gap junction proteins Cx26 and Cx31. | Liu XZ | Human genetics | 2009 | PMID: 19050930 |
| Lack of association between Connexin 31 (GJB3) alterations and sensorineural deafness in Austria. | Frei K | Hearing research | 2004 | PMID: 15276679 |
| Defective trafficking and cell death is characteristic of skin disease-associated connexin 31 mutations. | Di WL | Human molecular genetics | 2002 | PMID: 12165562 |
| Connexin 31 (GJB3) is expressed in the peripheral and auditory nerves and causes neuropathy and hearing impairment. | López-Bigas N | Human molecular genetics | 2001 | PMID: 11309368 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GJB3 | - | - | - | - |
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Text-mined citations for rs786200895 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 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.
NCBI staff reviewed the sequence information reported in PubMed 11309368 Fig. 1B to determine the location of this allele on the current reference sequence.