Variant classified as Uncertain Significance - Favor Benign. The p.Ala171Thr var iant in GJB2 has been previously reported in nine individuals with sensorineural hearing loss (Lin 2001, Najmabadi 2002, Wu 2002, Xiao 2004, Azaiez 2004, Putcha 2007, Samanich 2007, Han 2008, Bonyadi 2009, Bonyadi 2014, LMM data). However, a variant affecting the remaining copy of GJB2 was not identified in any of them . In addition, two individuals had cochlear malformations inconsistent with GJB 2-related hearing loss (Lin 2001, Wu 2002). One publication suggested that p.Ala 171Thr could be inherited in a dominant pattern (Xiao 2004); however, this is in consistent with findings from other studies. This variant has been identified i n two individuals with normal hearing (Samanich 2007, Han 2008) and has been ide ntified in 8/66556 European chromosomes by the Exome Aggregation Consortium (ExA C, http://exac.broadinstitute.org; dbSNP rs201004645). Computational prediction tools and conservation analysis suggest that the p.Ala171Thr variant may not imp act the protein, though this information is not predictive enough to rule out pa thogenicity. In summary, while the clinical significance of the p.Ala171Thr vari ant is uncertain, these data suggest that it is more likely to be benign.
ClinVar Genomic variation as it relates to human health
NM_004004.6(GJB2):c.511G>A (p.Ala171Thr)
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.
(7)
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
Uncertain significance(5); Benign(1)
Uncertain significance(5); Benign(1)
7
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_004004.6(GJB2):c.511G>A (p.Ala171Thr)
Variation ID: 44758 Accession: VCV000044758.11
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 13q12.11 13: 20189071 (GRCh38) [ NCBI UCSC ] 13: 20763210 (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 Sep 19, 2017 Jun 3, 2023 Apr 20, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_004004.6:c.511G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003995.2:p.Ala171Thr missense NC_000013.11:g.20189071C>T NC_000013.10:g.20763210C>T NG_008358.1:g.8905G>A LRG_1350:g.8905G>A LRG_1350t1:c.511G>A LRG_1350p1:p.Ala171Thr - Protein change
- A171T
- Other names
- -
- Canonical SPDI
- NC_000013.11:20189070:C:T
-
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.
-
0.00040 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00008
The Genome Aggregation Database (gnomAD), exomes 0.00013
The Genome Aggregation Database (gnomAD) 0.00014
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
Trans-Omics for Precision Medicine (TOPMed) 0.00018
1000 Genomes Project 30x 0.00031
1000 Genomes Project 0.00040
- Links
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 |
576 | 645 | |
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) |
criteria provided, multiple submitters, no conflicts
|
Apr 20, 2023 | RCV000037862.7 | |
| Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
May 28, 2019 | RCV000505525.5 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Apr 26, 2022 | RCV002513485.2 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(May 09, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Deafness, autosomal recessive 1A
Affected status: yes
Allele origin:
germline
|
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000599757.1
First in ClinVar: Sep 19, 2017 Last updated: Sep 19, 2017 |
Number of individuals with the variant: 1
|
|
|
Uncertain significance
(Nov 14, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 1A
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000795427.1
First in ClinVar: Sep 19, 2017 Last updated: Sep 19, 2017 |
|
|
|
Uncertain significance
(Jun 23, 2016)
|
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: SCV000061524.5
First in ClinVar: May 03, 2013 Last updated: Apr 09, 2018 |
Comment:
Variant classified as Uncertain Significance - Favor Benign. The p.Ala171Thr var iant in GJB2 has been previously reported in nine individuals with sensorineural hearing loss … (more)
Variant classified as Uncertain Significance - Favor Benign. The p.Ala171Thr var iant in GJB2 has been previously reported in nine individuals with sensorineural hearing loss (Lin 2001, Najmabadi 2002, Wu 2002, Xiao 2004, Azaiez 2004, Putcha 2007, Samanich 2007, Han 2008, Bonyadi 2009, Bonyadi 2014, LMM data). However, a variant affecting the remaining copy of GJB2 was not identified in any of them . In addition, two individuals had cochlear malformations inconsistent with GJB 2-related hearing loss (Lin 2001, Wu 2002). One publication suggested that p.Ala 171Thr could be inherited in a dominant pattern (Xiao 2004); however, this is in consistent with findings from other studies. This variant has been identified i n two individuals with normal hearing (Samanich 2007, Han 2008) and has been ide ntified in 8/66556 European chromosomes by the Exome Aggregation Consortium (ExA C, http://exac.broadinstitute.org; dbSNP rs201004645). Computational prediction tools and conservation analysis suggest that the p.Ala171Thr variant may not imp act the protein, though this information is not predictive enough to rule out pa thogenicity. In summary, while the clinical significance of the p.Ala171Thr vari ant is uncertain, these data suggest that it is more likely to be benign. (less)
Number of individuals with the variant: 2
|
|
|
Benign
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 1A
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001138906.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
|
Uncertain significance
(Apr 26, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003299681.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 171 of the GJB2 protein (p.Ala171Thr). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 171 of the GJB2 protein (p.Ala171Thr). This variant is present in population databases (rs201004645, gnomAD 0.02%). This missense change has been observed in individual(s) with GJB2-related conditions (PMID: 11438992, 15603707). ClinVar contains an entry for this variant (Variation ID: 44758). 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 not expected to disrupt GJB2 protein function. 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
(Apr 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003929343.1
First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023 |
Comment:
Variant summary: GJB2 c.511G>A (p.Ala171Thr) results in a non-conservative amino acid change located in the Gap junction protein, cysteine-rich domain (IPR019570) of the encoded protein … (more)
Variant summary: GJB2 c.511G>A (p.Ala171Thr) results in a non-conservative amino acid change located in the Gap junction protein, cysteine-rich domain (IPR019570) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 251052 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in GJB2 causing Non-Syndromic Hearing Loss (0.00013 vs 0.00034), allowing no conclusion about variant significance. c.511G>A has been reported in the literature in individuals affected with Non-Syndromic Hearing Loss (e.g. Wu_2002, Kashef_2015, Carranza_2016) and palmoplantar keratoderma (Harjama_2021). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters have assessed the variant since 2014: one classified the variant as benign, and five as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
|
|
|
Uncertain significance
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Autosomal recessive deafness type 1A
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001463362.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
Comment:
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 171 of the GJB2 protein (p.Ala171Thr). This variant is present in population databases (rs201004645, gnomAD 0.02%). This missense change has been observed in individual(s) with GJB2-related conditions (PMID: 11438992, 15603707). ClinVar contains an entry for this variant (Variation ID: 44758). 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 not expected to disrupt GJB2 protein function. 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:
Variant summary: GJB2 c.511G>A (p.Ala171Thr) results in a non-conservative amino acid change located in the Gap junction protein, cysteine-rich domain (IPR019570) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 251052 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in GJB2 causing Non-Syndromic Hearing Loss (0.00013 vs 0.00034), allowing no conclusion about variant significance. c.511G>A has been reported in the literature in individuals affected with Non-Syndromic Hearing Loss (e.g. Wu_2002, Kashef_2015, Carranza_2016) and palmoplantar keratoderma (Harjama_2021). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters have assessed the variant since 2014: one classified the variant as benign, and five as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
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:
Variant classified as Uncertain Significance - Favor Benign. The p.Ala171Thr var iant in GJB2 has been previously reported in nine individuals with sensorineural hearing loss (Lin 2001, Najmabadi 2002, Wu 2002, Xiao 2004, Azaiez 2004, Putcha 2007, Samanich 2007, Han 2008, Bonyadi 2009, Bonyadi 2014, LMM data). However, a variant affecting the remaining copy of GJB2 was not identified in any of them . In addition, two individuals had cochlear malformations inconsistent with GJB 2-related hearing loss (Lin 2001, Wu 2002). One publication suggested that p.Ala 171Thr could be inherited in a dominant pattern (Xiao 2004); however, this is in consistent with findings from other studies. This variant has been identified i n two individuals with normal hearing (Samanich 2007, Han 2008) and has been ide ntified in 8/66556 European chromosomes by the Exome Aggregation Consortium (ExA C, http://exac.broadinstitute.org; dbSNP rs201004645). Computational prediction tools and conservation analysis suggest that the p.Ala171Thr variant may not imp act the protein, though this information is not predictive enough to rule out pa thogenicity. In summary, while the clinical significance of the p.Ala171Thr vari ant is uncertain, these data suggest that it is more likely to be benign.
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 171 of the GJB2 protein (p.Ala171Thr). This variant is present in population databases (rs201004645, gnomAD 0.02%). This missense change has been observed in individual(s) with GJB2-related conditions (PMID: 11438992, 15603707). ClinVar contains an entry for this variant (Variation ID: 44758). 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 not expected to disrupt GJB2 protein function. 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:
Variant summary: GJB2 c.511G>A (p.Ala171Thr) results in a non-conservative amino acid change located in the Gap junction protein, cysteine-rich domain (IPR019570) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 251052 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in GJB2 causing Non-Syndromic Hearing Loss (0.00013 vs 0.00034), allowing no conclusion about variant significance. c.511G>A has been reported in the literature in individuals affected with Non-Syndromic Hearing Loss (e.g. Wu_2002, Kashef_2015, Carranza_2016) and palmoplantar keratoderma (Harjama_2021). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters have assessed the variant since 2014: one classified the variant as benign, and five as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Hereditary palmoplantar keratoderma - phenotypes and mutations in 64 patients. | Harjama L | Journal of the European Academy of Dermatology and Venereology : JEADV | 2021 | PMID: 33914963 |
| A Mayan founder mutation is a common cause of deafness in Guatemala. | Carranza C | Clinical genetics | 2016 | PMID: 26346709 |
| Clinical application of a custom AmpliSeq library and ion torrent PGM sequencing to comprehensive mutation screening for deafness genes. | Nishio SY | Genetic testing and molecular biomarkers | 2015 | PMID: 25587757 |
| Finding mutation within non-coding region of GJB2 reveals its importance in genetic testing of hearing loss in Iranian population. | Kashef A | International journal of pediatric otorhinolaryngology | 2015 | PMID: 25555641 |
| Spectrum and frequency of GJB2 mutations causing deafness in the northwest of Iran. | Bonyadi MJ | International journal of pediatric otorhinolaryngology | 2014 | PMID: 24529908 |
| GJB2 and mitochondrial DNA 1555A>G mutations in students with hearing loss in the Hubei Province of China. | Chen G | International journal of pediatric otorhinolaryngology | 2011 | PMID: 21777984 |
| Clinical comparison of hearing-impaired patients with DFNB1 against heterozygote carriers of connexin 26 mutations. | Lipan M | The Laryngoscope | 2011 | PMID: 21287563 |
| Mutation analysis of familial GJB2-related deafness in Iranian Azeri Turkish patients. | Bonyadi M | Genetic testing and molecular biomarkers | 2009 | PMID: 19715472 |
| Carrier frequency of GJB2 (connexin-26) mutations causing inherited deafness in the Korean population. | Han SH | Journal of human genetics | 2008 | PMID: 19043807 |
| 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 |
| Mutations in GJB2, GJB6, and mitochondrial DNA are rare in African American and Caribbean Hispanic individuals with hearing impairment. | Samanich J | American journal of medical genetics. Part A | 2007 | PMID: 17357124 |
| GJB2 (Cx26) gene mutations in Chinese patients with congenital sensorineural deafness and a report of one novel mutation. | Xiao ZA | Chinese medical journal | 2004 | PMID: 15603707 |
| GJB2: the spectrum of deafness-causing allele variants and their phenotype. | Azaiez H | Human mutation | 2004 | PMID: 15365987 |
| Effectiveness of sequencing connexin 26 (GJB2) in cases of familial or sporadic childhood deafness referred for molecular diagnostic testing. | Wu BL | Genetics in medicine : official journal of the American College of Medical Genetics | 2002 | PMID: 12172394 |
| GJB2 mutations in Iranians with autosomal recessive non-syndromic sensorineural hearing loss. | Najmabadi H | Human mutation | 2002 | PMID: 11968091 |
| Assessment of denaturing high-performance liquid chromatography (DHPLC) in screening for mutations in connexin 26 (GJB2). | Lin D | Human mutation | 2001 | PMID: 11438992 |
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Text-mined citations for rs201004645 ...
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 Sep 29, 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.