VCV000094388.30 - ClinVar

NM_004004.6(GJB2):c.-15C>T

Germline

Classification

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.

(13)

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.

Benign/Likely benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004004.6(GJB2):c.-15C>T

Variation ID: 94388 Accession: VCV000094388.30

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 13q12.11 13: 20189596 (GRCh38) [ NCBI UCSC ] 13: 20763735 (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	Oct 2, 2016	Sep 29, 2024	Sep 27, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_004004.6:c.-15C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		5 prime UTR
NC_000013.11:g.20189596G>A
NC_000013.10:g.20763735G>A
NG_008358.1:g.8380C>T
LRG_1350:g.8380C>T
LRG_1350t1:c.-15C>T

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000013.11:20189595:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

0.01717 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00383

Exome Aggregation Consortium (ExAC) 0.00473

The Genome Aggregation Database (gnomAD) 0.01589

Trans-Omics for Precision Medicine (TOPMed) 0.01714

1000 Genomes Project 0.01717

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.01753

1000 Genomes Project 30x 0.01889

Links

ClinGen: CA147793 dbSNP: rs72561725 VarSome

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
Gene	OMIM	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	572	639

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.
not specified	Benign (4)	criteria provided, multiple submitters, no conflicts	Feb 5, 2018	RCV000080361.28
Ichthyosis, hystrix-like, with hearing loss	Benign (1)	criteria provided, single submitter	Jan 12, 2018	RCV000266756.13
Autosomal recessive nonsyndromic hearing loss 1A	Likely benign (2)	criteria provided, single submitter	Jan 12, 2018	RCV000297256.14
Autosomal dominant nonsyndromic hearing loss 3A	Benign (1)	criteria provided, single submitter	Jan 12, 2018	RCV000303188.13
not provided	Benign/Likely benign (4)	criteria provided, multiple submitters, no conflicts	Sep 27, 2023	RCV000711346.25
Nonsyndromic genetic hearing loss	Benign (1)	criteria provided, single submitter	Aug 31, 2020	RCV001257149.9

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.
Benign (Feb 05, 2018)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000730583.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Benign (Dec 07, 2012)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000112257.8 First in ClinVar: Jan 17, 2014 Last updated: Apr 09, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GJB2 Number of individuals with the variant: 20 Sex: mixed
Benign (Apr 27, 2019)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000841698.2 First in ClinVar: Oct 20, 2018 Last updated: Jan 18, 2020	Publications: PubMed (15) PubMed: 25401782‚ 26778469‚ 14722929‚ 19125024‚ 21392827‚ 25162826‚ 27501294‚ 17357124‚ 20381175‚ 17041943‚ 24706568‚ 26409293‚ 19081147‚ 23684175‚ 24596593
Benign (Jan 12, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Ichthyosis, hystrix-like, with hearing loss Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000383059.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Likely benign (Jan 12, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Autosomal recessive nonsyndromic hearing loss 1A Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000383057.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
Benign (Jan 12, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Autosomal dominant nonsyndromic hearing loss 3A Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000383060.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000309909.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Benign (Jun 14, 2013)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000198170.4 First in ClinVar: Jan 30, 2015 Last updated: Apr 09, 2018	Comment: -15C>T in Exon 02 of GJB2: This variant is not expected to have clinical signifi cance because it has been identified in 5.2% (228/4406) of … (more) -15C>T in Exon 02 of GJB2: This variant is not expected to have clinical signifi cance because it has been identified in 5.2% (228/4406) of African American chro mosomes from a broad population by the NHLBI Exome Sequencing Project (http://ev s.gs.washington.edu) (less) Number of individuals with the variant: 21
Benign (Aug 31, 2020)	criteria provided, single submitter (ClinGen HL ACMG Specifications v1) Method: clinical testing	Nonsyndromic hearing loss and deafness (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	INGEBI, INGEBI / CONICET Accession: SCV001433665.1 First in ClinVar: Sep 27, 2020 Last updated: Sep 27, 2020	Publications: PubMed (2) PubMed: 27501294‚ 21392827 Comment: Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the filtering allele frequency of the c.-15C>T variant in GJB2 gene is 4,86% (1271/24918 … (more) Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the filtering allele frequency of the c.-15C>T variant in GJB2 gene is 4,86% (1271/24918 African chromosomes with 95%CI) from Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/). This is a high enough frequency, based on the thresholds defined by the ClinGen Hearing Loss Expert Panel, for autosomal recessive hearing loss variants to apply for BA1 rule. This variant is frequent (above 6%) in controls subjects from different African populations (PS4 not met, PMID: 27501294, 21392827) Benign computational verdict prediction from DANN and CADD predictors and no conservation between species (GERPscore:-5.08) applying to BP4 rule. In summary, this variant meets criteria to be classified as benign for non-syndromic hearing loss (BA1, BP4). (less) Number of individuals with the variant: 1 Clinical Features: Postlingual moderate hearing loss (present) Family history: yes Sex: female Ethnicity/Population group: Latino Geographic origin: Argentina Tissue: blood Secondary finding: no
Benign (Nov 14, 2021)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000603816.4 First in ClinVar: Oct 02, 2016 Last updated: Jan 08, 2022
Benign (Sep 27, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001733243.4 First in ClinVar: Jun 15, 2021 Last updated: Feb 14, 2024
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005219306.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Autosomal recessive deafness type 1A Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001455336.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
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Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Comment:

-15C>T in Exon 02 of GJB2: This variant is not expected to have clinical signifi cance because it has been identified in 5.2% (228/4406) of African American chro mosomes from a broad population by the NHLBI Exome Sequencing Project (http://ev s.gs.washington.edu)

Comment:

Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the filtering allele frequency of the c.-15C>T variant in GJB2 gene is 4,86% (1271/24918 African chromosomes with 95%CI) from Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/). This is a high enough frequency, based on the thresholds defined by the ClinGen Hearing Loss Expert Panel, for autosomal recessive hearing loss variants to apply for BA1 rule. This variant is frequent (above 6%) in controls subjects from different African populations (PS4 not met, PMID: 27501294, 21392827) Benign computational verdict prediction from DANN and CADD predictors and no conservation between species (GERPscore:-5.08) applying to BP4 rule. In summary, this variant meets criteria to be classified as benign for non-syndromic hearing loss (BA1, BP4).

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:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Genetic Basis of Nonsyndromic Sensorineural Hearing Loss in the Sub-Saharan African Island Population of São Tomé and Príncipe: The Role of the DFNB1 Locus?	Caroça C	Omics : a journal of integrative biology	2016	PMID: 27501294
Prevalence and audiological profiles of GJB2 mutations in a large collective of hearing impaired patients.	Burke WF	Hearing research	2016	PMID: 26778469
Mutation spectrum of autosomal recessive non-syndromic hearing loss in central Iran.	Haghighat-Nia A	International journal of pediatric otorhinolaryngology	2015	PMID: 26409293
New and rare GJB2 alleles in patients with nonsyndromic sensorineural hearing impairment: a genotype/auditory phenotype correlation.	Stanghellini I	Genetic testing and molecular biomarkers	2014	PMID: 25401782
Sequencing of GJB2 in Cameroonians and Black South Africans and comparison to 1000 Genomes Project Data Support Need to Revise Strategy for Discovery of Nonsyndromic Deafness Genes in Africans.	Bosch J	Omics : a journal of integrative biology	2014	PMID: 25162826
Connexin gene mutations among Ugandan patients with nonsyndromic sensorineural hearing loss.	Javidnia H	The Laryngoscope	2014	PMID: 24706568
Strategies for genetic study of hearing loss in the Brazilian northeastern region.	Melo US	International journal of molecular epidemiology and genetics	2014	PMID: 24596593
Non-syndromic hearing impairment in a multi-ethnic population of Northeastern Brazil.	Manzoli GN	International journal of pediatric otorhinolaryngology	2013	PMID: 23684175
Absence of GJB2 gene mutations, the GJB6 deletion (GJB6-D13S1830) and four common mitochondrial mutations in nonsyndromic genetic hearing loss in a South African population.	Kabahuma RI	International journal of pediatric otorhinolaryngology	2011	PMID: 21392827
GJB2 mutation spectrum in 209 hearing impaired individuals of predominantly Caribbean Hispanic and African descent.	Shan J	International journal of pediatric otorhinolaryngology	2010	PMID: 20381175
Prevalence of GJB2 (connexin-26) and GJB6 (connexin-30) mutations in a cohort of 300 Brazilian hearing-impaired individuals: implications for diagnosis and genetic counseling.	Batissoco AC	Ear and hearing	2009	PMID: 19125024
Genetic evaluation of American minority pediatric cochlear implant recipients.	Fischer TC	International journal of pediatric otorhinolaryngology	2009	PMID: 19081147
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
DNA sequence analysis of GJB2, encoding connexin 26: observations from a population of hearing impaired cases and variable carrier rates, complex genotypes, and ethnic stratification of alleles among controls.	Tang HY	American journal of medical genetics. Part A	2006	PMID: 17041943
Low frequency of deafness-associated GJB2 variants in Kenya and Sudan and novel GJB2 variants.	Gasmelseed NMA	Human mutation	2004	PMID: 14722929
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GJB2	-	-	-	-
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Text-mined citations for rs72561725 ...

These 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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_004004.6(GJB2):c.-15C>T

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs72561725 ...