ClinVar Genomic variation as it relates to human health
NM_004004.6(GJB2):c.563A>G (p.Lys188Arg)
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
-
NM_004004.6(GJB2):c.563A>G (p.Lys188Arg)
Variation ID: 429984 Accession: VCV000429984.9
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 13q12.11 13: 20189019 (GRCh38) [ NCBI UCSC ] 13: 20763158 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 2, 2017 Apr 6, 2024 Mar 28, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_004004.6(GJB2):c.563A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_004004.6:c.563A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003995.2:p.Lys188Arg missense NC_000013.11:g.20189019T>C NC_000013.10:g.20763158T>C NG_008358.1:g.8957A>G LRG_1350:g.8957A>G LRG_1350t1:c.563A>G LRG_1350p1:p.Lys188Arg - Protein change
- K188R
- Other names
- -
- Canonical SPDI
- NC_000013.11:20189018:T:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 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 | ||
---|---|---|---|---|---|---|
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. |
|||
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
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. |
---|---|---|---|---|
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Oct 26, 2023 | RCV000493772.6 | |
Likely pathogenic (1) |
reviewed by expert panel
|
Mar 28, 2024 | RCV001004776.2 |
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. |
|
---|---|---|---|---|---|
Likely Pathogenic
(Mar 28, 2024)
|
reviewed by expert panel
Method: curation
|
Nonsyndromic genetic hearing loss
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen Hearing Loss Variant Curation Expert Panel
Accession: SCV001164258.2
First in ClinVar: Mar 01, 2020 Last updated: Apr 06, 2024 |
Comment:
The NM_004004.6(GJB2):c.563A>G variant in GJB2 is a missense variant predicted to cause substitution of lysine by arginine at amino acid 188 (p.Lys188Arg). The highest population … (more)
The NM_004004.6(GJB2):c.563A>G variant in GJB2 is a missense variant predicted to cause substitution of lysine by arginine at amino acid 188 (p.Lys188Arg). The highest population minor allele frequency of the variant is 0.00025% (3/1180000) in the European (non-Finnish) population in gnomAD v.4.0.0 (PM2_Supporting). This variant has been reported in at least three probands with hearing loss (2.5 PM3_Strong points). Two probands were compound heterozygous (one confirmed trans, the other one assumed trans) with the pathogenic c.35delG, p.G12Vfs variant (Clinvar ID: 17004, PMID 17666888, internal data from GeneDx). Another proband was compound heterozygous for the pathogenic variant p.Leu90Pro (ClinVar ID: 17016, University of Minnesota internal data). The REVEL computational prediction analysis tool produced a score of 0.9 meeting PP3. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PM2_Supporting, PM3_Strong, PP3 (VCEP specifications version 2; 01.17.2024). (less)
|
|
Uncertain significance
(Apr 21, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000698268.1
First in ClinVar: Jul 02, 2017 Last updated: Jul 02, 2017 |
Comment:
Variant summary: The c.563A>G variant involves the alteration of one of 5 invariant amino acid residues in the Connexin domain of GJB2 and 4/5 in … (more)
Variant summary: The c.563A>G variant involves the alteration of one of 5 invariant amino acid residues in the Connexin domain of GJB2 and 4/5 in silico tools predict a pathogenic outcome. The variant is absent from the large, broad ExAC control population and has been reported in the literature in two patients with hearing loss, at least one of whom also carried the known pathogenic GJB2 c.35delG variant in trans (Putcha_2007). Additionally, When expressed in HeLa cells, the K188R mutant failed to localize to cell membrane (Ambrosi_2013). Based on the highly conserved nature of the amino acid at position 563, despite limited clinical and functional data, this variant has been classified as a VUS - possibly pathogenic until additional evidence becomes available. (less)
|
|
Pathogenic
(Apr 24, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000582691.3
First in ClinVar: Jul 02, 2017 Last updated: Jul 02, 2017 |
Comment:
The K188R variant in the GJB2 gene has been reported previously in association with autosomal recessive nonsyndromic sensorineural hearing loss (Putcha et al., 2007). The … (more)
The K188R variant in the GJB2 gene has been reported previously in association with autosomal recessive nonsyndromic sensorineural hearing loss (Putcha et al., 2007). The K188R variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The K188R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, missense variants in nearby residues (R184G, R184W, R184Q, R184P, T186M, T186K, V190D) have been reported in the Human Gene Mutation Database in association with hearing loss (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret K188R as a pathogenic variant. (less)
|
|
Pathogenic
(Oct 26, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV002179978.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 188 of the GJB2 protein (p.Lys188Arg). … (more)
This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 188 of the GJB2 protein (p.Lys188Arg). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with autosomal recessive nonsyndromic sensorineural deafness (PMID: 17666888; external communication). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 429984). 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: 23967136). For these reasons, this variant has been classified as Pathogenic. (less)
|
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 |
---|---|---|---|---|
Bioinformatic Analysis of GJB2 Gene Missense Mutations. | Yilmaz A | Cell biochemistry and biophysics | 2015 | PMID: 25388846 |
Analysis of trafficking, stability and function of human connexin 26 gap junction channels with deafness-causing mutations in the fourth transmembrane helix. | Ambrosi C | PloS one | 2013 | PMID: 23967136 |
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 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/4695ee4b-08a2-4fd3-8d4a-f5d1dad3695c | - | - | - | - |
Text-mined citations for rs1131691709 ...
HelpRecord last updated Apr 06, 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.