ClinVar Genomic variation as it relates to human health
NM_004004.6(GJB2):c.571T>C (p.Phe191Leu)
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.571T>C (p.Phe191Leu)
Variation ID: 44760 Accession: VCV000044760.29
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 13q12.11 13: 20189011 (GRCh38) [ NCBI UCSC ] 13: 20763150 (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 Jan 31, 2015 Jan 26, 2024 Sep 24, 2018 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_004004.6:c.571T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003995.2:p.Phe191Leu missense NC_000013.11:g.20189011A>G NC_000013.10:g.20763150A>G NG_008358.1:g.8965T>C LRG_1350:g.8965T>C LRG_1350t1:c.571T>C LRG_1350p1:p.Phe191Leu P29033:p.Phe191Leu - Protein change
- F191L
- Other names
- NM_004004.5(GJB2):c.571T>C
- Canonical SPDI
- NC_000013.11:20189010:A:G
-
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.
-
0.00020 (G)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00009
The Genome Aggregation Database (gnomAD), exomes 0.00014
Exome Aggregation Consortium (ExAC) 0.00015
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
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 | 619 |
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. |
---|---|---|---|---|
Uncertain significance (2) |
reviewed by expert panel
|
Sep 24, 2018 | RCV000037865.16 | |
Uncertain significance (2) |
criteria provided, single submitter
|
Jun 2, 2023 | RCV000674539.10 | |
Pathogenic (1) |
no assertion criteria provided
|
Dec 10, 2012 | RCV000678891.9 | |
Likely benign (2) |
criteria provided, multiple submitters, no conflicts
|
Jul 28, 2021 | RCV001002772.10 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
Sep 22, 2023 | RCV001555873.20 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Dec 6, 2021 | RCV002477097.8 |
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. |
|
---|---|---|---|---|---|
Uncertain significance
(Sep 24, 2018)
|
reviewed by expert panel
Method: curation
|
Not Specified
Affected status: unknown
Allele origin:
germline
|
ClinGen Hearing Loss Variant Curation Expert Panel
Accession: SCV000886635.2
First in ClinVar: Mar 04, 2019 Last updated: Dec 11, 2022 |
Comment:
The c.571T>C (p.Phe191Leu) variant in GJB2 has been reported in over 19 Asian probands in the literature. However, a case control comparison using Chi-squared analysis … (more)
The c.571T>C (p.Phe191Leu) variant in GJB2 has been reported in over 19 Asian probands in the literature. However, a case control comparison using Chi-squared analysis did not show a statistical significance between cases and controls in the published studies, or between cases and East Asians in gnomAD (case chromosomes= 19/16415, control chromosomes = 6/8626, 36/18870 East Asian chromosomes in gnomAD; PMIDs 19366456, 15700112, 23826813, 27247933, 27792752, 12792423, 12560944, 19043807, 27627659, 20497192 and https://doi.org/10.1016/S1672-2930(07)50004-8). The filtering allele frequency of the p.Phe191Leu variant in the GJB2 gene is 0.14% for East Asian chromosomes in gnomAD (36/18870 with 95% CI), which is a higher frequency than would be expected for an autosomal recessive pathogenic variant based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting). This variant has been detected in 1 individual with hearing loss who was homozygous for the variant, and in 4 compound heterozygous individuals who had a second pathogenic GJB2 variant identified (3 with p.Val37Ile and 1 with c.235delC) (Oguchi 2005 PMID: 15700112; ARUP SCV000603821; Partners Lab for Molecular Medicine SCV000061527). Phase was not confirmed for any of these individuals. It is possible that these homozygous and compound heterozygous observations are due to the relatively high allele frequencies of these variants in gnomAD and therefore PM3 was downgraded (PM3_Supporting). In addition, this variant was reported in the homozygous state in a normal hearing parent (BS2, Wattanasirichiagoon 2004, PMID 15479191). Computational prediction analysis using REVEL suggests that the variant may impact the protein (PP3). Two in vitro functional studies demonstrates that this variant resulted in abnormal protein trafficking and retention of the protein in the endoplasmic reticulum; however, further electrical coupling studies were not performed (PS3_Supporting; PMID: 23967136, 26749107). In summary, due to conflicting evidence, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1_Supporting, BS2, PM3_Supporting, PS3_Supporting, PP3. (less)
|
|
Likely benign
(Jun 29, 2011)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000061527.5
First in ClinVar: May 03, 2013 Last updated: Jan 31, 2015 |
Comment:
Phe191Leu in exon 2 of GJB2: This variant is not expected to have clinical signi ficance due to its occurrence at an equal frequency in … (more)
Phe191Leu in exon 2 of GJB2: This variant is not expected to have clinical signi ficance due to its occurrence at an equal frequency in the general population (H an 2008, Dahl 2006, Dai 2009, Hwa 2003, Ohtsuka 2003, Posukh 2005, Wattanasirich aigoon 2004). (less)
Number of individuals with the variant: 3
|
|
Likely pathogenic
(Aug 20, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000603821.2
First in ClinVar: Jan 31, 2015 Last updated: Jan 26, 2021 |
Comment:
The GJB2 c.571T>C; p.Phe191Leu variant (rs397516878) is reported in the literature in individuals affected with hearing loss but also in normal hearing controls (Dahl 2006, … (more)
The GJB2 c.571T>C; p.Phe191Leu variant (rs397516878) is reported in the literature in individuals affected with hearing loss but also in normal hearing controls (Dahl 2006, Hwa 2003, Oguchi 2005, Ohtsuka 2003, Posukh 2019, Shi 2016, Wattanasirichaigoon 2004, Wei 2013). This variant has been observed in the compound heterozygous state in affected individuals tested at ARUP Laboratories and has been reported in the homozygous state in a mildly affected individual (Oguchi 2005), but it is also reported in a homozygous individual with normal hearing (Wattanasirichaigoon 2005). This variant is found in the East Asian population with an overall allele frequency of 0.19% (37/19954 alleles) in the Genome Aggregation Database. The phenylalanine at codon 191 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Indeed, functional studies suggest the variant protein is mislocalized in cultured cells (Ambrosi 2013); however, its ability to form functional gap junctions has not been adequately tested. Due to limited and conflicting information, the clinical significance of the p.Phe191Leu variant is uncertain at this time. References: Ambrosi C et al. Analysis of trafficking, stability and function of human connexin 26 gap junction channels with deafness-causing mutations in the fourth transmembrane helix. PLoS One. 2013; 8(8):e70916. Dahl HH et al. The contribution of GJB2 mutations to slight or mild hearing loss in Australian elementary school children. J Med Genet. 2006;43(11):850-855. Hwa HL et al. Mutation spectrum of the connexin 26 (GJB2) gene in Taiwanese patients with prelingual deafness. Genet Med. 2003;5(3):161-165. Oguchi T et al. Clinical features of patients with GJB2 (connexin 26) mutations: severity of hearing loss is correlated with genotypes and protein expression patterns. J Hum Genet. 2005;50(2):76-83. Ohtsuka A et al. GJB2 deafness gene shows a specific spectrum of mutations in Japan, including a frequent founder mutation. Hum Genet. 2003;112(4):329-333. Posukh OL et al. Unique Mutational Spectrum of the GJB2 Gene and its Pathogenic Contribution to Deafness in Tuvinians (Southern Siberia, Russia): A High Prevalence of Rare Variant c.516G>C (p.Trp172Cys). Genes (Basel). 2019;10(6):429. Shi L et al. Prevalence of GJB2 gene mutation in 330 cochlear implant patients in the Jiangsu province. J Laryngol Otol. 2016;130(10):902-906. (less)
|
|
Uncertain significance
(Dec 06, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
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
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002793319.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
Uncertain significance
(May 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics Inc
Accession: SCV004229559.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is … (more)
Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 23967136, 26749107) (less)
|
|
Likely benign
(-)
|
criteria provided, single submitter
Method: case-control
|
Autosomal dominant nonsyndromic hearing loss 3A
Affected status: no
Allele origin:
paternal
|
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital
Accession: SCV000992417.1
First in ClinVar: Feb 16, 2020 Last updated: Feb 16, 2020 |
Number of individuals with the variant: 2
Clinical Features:
Hearing loss (present) , Multiple lentigines (present) , Ocular hypertelorism (present)
|
|
Likely benign
(Jul 28, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal dominant nonsyndromic hearing loss 3A
(Autosomal dominant inheritance)
Affected status: no
Allele origin:
germline
|
Pars Genome Lab
Accession: SCV001761671.1
First in ClinVar: Jul 30, 2021 Last updated: Jul 30, 2021 |
Age: 40-49 years
|
|
Uncertain significance
(Nov 02, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV003268178.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 191 of the GJB2 protein (p.Phe191Leu). … (more)
This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 191 of the GJB2 protein (p.Phe191Leu). This variant is present in population databases (rs397516878, gnomAD 0.2%). This missense change has been observed in individual(s) with hearing loss (PMID: 12560944, 12792423, 15479191, 15790391, 26252218). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 44760). 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. Experimental studies have shown that this missense change affects GJB2 function (PMID: 23967136, 26749107). 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)
|
|
Uncertain significance
(Jun 02, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 1A
Affected status: yes
Allele origin:
germline
|
Integrating Genomics into Medicine, Frazer Institute, University Of Queensland
Accession: SCV003935277.1
First in ClinVar: Jul 01, 2023 Last updated: Jul 01, 2023 |
|
|
Uncertain significance
(Sep 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001777361.6
First in ClinVar: Aug 13, 2021 Last updated: Sep 30, 2023 |
Comment:
Observed frequently in unrelated patients of Asian ancestry with sensorineural hearing loss, often in the heterozygous state with no second GJB2 variant identified (Hwa et … (more)
Observed frequently in unrelated patients of Asian ancestry with sensorineural hearing loss, often in the heterozygous state with no second GJB2 variant identified (Hwa et al., 2003; Chen et al., 2009; Wei et al., 2013; Luo et al., 2017); Reported in published literature in the homozygous state in a patient with mild sloping to severe hearing loss, and in the homozygous state in a clinically unaffected adult (Wattanasirichaigoon et al., 2004; Oguchi et al., 2005); Observed in a patient with bilateral profound sensorineural hearing loss who also harbored a de novo insertion/deletion variant involving the EYA1 gene (Zheng et al., 2021); Published functional studies demonstrate a damaging effect due to mislocalization of the protein, however, electrical coupling studies were not performed (Kim et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Classified as a variant of uncertain significance by the ClinGen Hearing Loss Expert Panel (SCV000886635.1; Oza et al., 2018); This variant is associated with the following publications: (PMID: 12772454, 22384008, 24158611, 30245029, 12560944, 19366456, 20497192, 24256046, 23967136, 12792423, 15790391, 19043807, 25808784, 25388846, 16840571, 27792752, 27627659, 27247933, 31195736, 21366436, 26252218, 31992338, 31160754, 29871260, 15700112, 15479191, 19707039, 23826813, 28786104, 34403091, 33880118, 26749107, 31581539, 35212567, 37373495) (less)
|
|
Uncertain significance
(May 09, 2018)
|
no assertion criteria provided
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 1A
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000799891.2
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
|
|
Pathogenic
(Dec 10, 2012)
|
no assertion criteria provided
Method: clinical testing
|
Hearing loss
Affected status: yes
Allele origin:
germline
|
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital
Accession: SCV000805084.1
First in ClinVar: Sep 14, 2018 Last updated: Sep 14, 2018 |
|
|
click to load more click to collapse |
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 |
---|---|---|---|---|
Social Health Insurance-Based Simultaneous Screening for 154 Mutations in 19 Deafness Genes Efficiently Identified Causative Mutations in Japanese Hearing Loss Patients. | Mori K | PloS one | 2016 | PMID: 27627659 |
Prevalence of GJB2 gene mutation in 330 cochlear implant patients in the Jiangsu province. | Shi L | The Journal of laryngology and otology | 2016 | PMID: 27534436 |
Mutation Analysis of the Common Deafness Genes in Patients with Nonsyndromic Hearing Loss in Linyi by SNPscan Assay. | Zhang F | BioMed research international | 2016 | PMID: 27247933 |
Application of a New Genetic Deafness Microarray for Detecting Mutations in the Deaf in China. | Wu H | PloS one | 2016 | PMID: 27018795 |
The pathological effects of connexin 26 variants related to hearing loss by in silico and in vitro analysis. | Kim HR | Human genetics | 2016 | PMID: 26749107 |
Mutation Spectrum of Common Deafness-Causing Genes in Patients with Non-Syndromic Deafness in the Xiamen Area, China. | Jiang Y | PloS one | 2015 | PMID: 26252218 |
Novel mutations in GJB6 and GJB2 in Clouston syndrome. | Liu YT | Clinical and experimental dermatology | 2015 | PMID: 25808784 |
Deafness gene variations in a 1120 nonsyndromic hearing loss cohort: molecular epidemiology and deafness mutation spectrum of patients in Japan. | Nishio SY | The Annals of otology, rhinology, and laryngology | 2015 | PMID: 25788563 |
Bioinformatic Analysis of GJB2 Gene Missense Mutations. | Yilmaz A | Cell biochemistry and biophysics | 2015 | PMID: 25388846 |
A rapid method for simultaneous multi-gene mutation screening in children with nonsyndromic hearing loss. | Du W | Genomics | 2014 | PMID: 25149764 |
Prevalence of GJB2 mutations in the Silk Road region of China and a report of three novel variants. | Du W | Acta oto-laryngologica | 2014 | PMID: 24256046 |
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 |
Genetic mutations of GJB2 and mitochondrial 12S rRNA in nonsyndromic hearing loss in Jiangsu Province of China. | Wei Q | Journal of translational medicine | 2013 | PMID: 23826813 |
GJB2 allele variants and the associated audiologic features identified in Chinese patients with less severe idiopathic hearing loss. | Zhang J | Genetic testing and molecular biomarkers | 2011 | PMID: 21366436 |
A large cohort study of GJB2 mutations in Japanese hearing loss patients. | Tsukada K | Clinical genetics | 2010 | PMID: 20497192 |
High prevalence of the connexin 26 (GJB2) mutation in Chinese cochlear implant recipients. | Chen D | ORL; journal for oto-rhino-laryngology and its related specialties | 2009 | PMID: 19707039 |
GJB2 mutation spectrum in 2,063 Chinese patients with nonsyndromic hearing impairment. | Dai P | Journal of translational medicine | 2009 | PMID: 19366456 |
Carrier frequency of GJB2 (connexin-26) mutations causing inherited deafness in the Korean population. | Han SH | Journal of human genetics | 2008 | PMID: 19043807 |
The contribution of GJB2 mutations to slight or mild hearing loss in Australian elementary school children. | Dahl HH | Journal of medical genetics | 2006 | PMID: 16840571 |
First molecular screening of deafness in the Altai Republic population. | Posukh O | BMC medical genetics | 2005 | PMID: 15790391 |
Clinical features of patients with GJB2 (connexin 26) mutations: severity of hearing loss is correlated with genotypes and protein expression patterns. | Oguchi T | Journal of human genetics | 2005 | PMID: 15700112 |
High prevalence of V37I genetic variant in the connexin-26 (GJB2) gene among non-syndromic hearing-impaired and control Thai individuals. | Wattanasirichaigoon D | Clinical genetics | 2004 | PMID: 15479191 |
Mutation spectrum of the connexin 26 (GJB2) gene in Taiwanese patients with prelingual deafness. | Hwa HL | Genetics in medicine : official journal of the American College of Medical Genetics | 2003 | PMID: 12792423 |
GJB2 deafness gene shows a specific spectrum of mutations in Japan, including a frequent founder mutation. | Ohtsuka A | Human genetics | 2003 | PMID: 12560944 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/3d336d40-28c9-4f51-b57c-d5a224b55959 | - | - | - | - |
click to load more click to collapse |
Text-mined citations for rs397516878 ...
HelpRecord last updated Mar 23, 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.