NM_004004.6(GJB2):c.-23+1G>A AND not provided

Germline classification:: Pathogenic (9 submissions)
Last evaluated:: Jan 31, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000418755.46

Allele description [Variation Report for NM_004004.6(GJB2):c.-23+1G>A]

NM_004004.6(GJB2):c.-23+1G>A

Gene:

GJB2:gap junction protein beta 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

13q12.11

Genomic location:

Preferred name:

NM_004004.6(GJB2):c.-23+1G>A

Other names:

IVS1+1G>A

HGVS:

NC_000013.11:g.20192782C>T
NG_008358.1:g.5194G>A
NM_004004.6:c.-23+1G>AMANE SELECT
LRG_1350t1:c.-23+1G>A
LRG_1350:g.5194G>A
NC_000013.10:g.20766921C>T
NM_004004.5:c.-23+1G>A
c.-23+1G>A
g.-3179G>A

Nucleotide change:

IVS1DS, G-A, +1

Links:

OMIM: 121011.0029; dbSNP: rs80338940

NCBI 1000 Genomes Browser:

rs80338940

Molecular consequence:

NM_004004.6:c.-23+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000516861	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Nov 3, 2021)	germline	clinical testing	Citation Link,
SCV000841702	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Mar 23, 2022)	unknown	clinical testing	PubMed (15) [See all records that cite these PMIDs] 10218527, 11935342, 24840842, 27481527, 27843504, 24959830, 21776002, 25012701, 27177978, 22567369, 19814620, 27224056, 24793888, 31346875, 26467025
SCV000957075	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 10218527, 24840842, 24959830, 27481527, 27843504, 21776002, 11935342, 17576681, 9536098, 28492532
SCV001156573	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Pathogenic (Feb 12, 2021)	germline	clinical testing	Citation Link,
SCV001245656	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Aug 1, 2017)	germline	clinical testing	Citation Link,
SCV001905675	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 15, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001951168	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001975771	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV002024266	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 21, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

GJB2 c.-23+1G>A mutation is second most common mutation among Iranian individuals with autosomal recessive hearing loss.

Zeinali S, Davoudi-Dehaghani E, Azadmehr S, DabbaghBagheri S, Bagherian H, Jamali M, Zafarghandimotlagh F, Masoodifard M, BandehiSarhaddi A, Rejali L, Sahebi S.

Eur Arch Otorhinolaryngol. 2015 Sep;272(9):2255-9. doi: 10.1007/s00405-014-3171-7. Epub 2014 Jul 11.

PubMed [citation]

PMID:: 25012701

Evaluation of electrocardiographic parameters in patients with hearing loss genotyped for the connexin 26 gene (GJB2) mutations.

Sanecka A, Biernacka EK, Sosna M, Mueller-Malesinska M, Ploski R, Skarzynski H, Piotrowicz R.

Braz J Otorhinolaryngol. 2017 Mar - Apr;83(2):176-182. doi: 10.1016/j.bjorl.2016.02.008. Epub 2016 Apr 22.

PubMed [citation]

PMID:: 27177978
PMCID:: PMC9442716

See all PubMed Citations (19)

Details of each submission

From GeneDx, SCV000516861.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Published functional studies indicate that this variant disrupts splicing and results in no gene transcription (Shahin et al., 2002); Also known IVS1+1G>A; This variant is associated with the following publications: (PMID: 24840842, 24959830, 25012701, 11935342, 31162818, 16650079, 32708339, 10218527, 24793888, 27843504, 27481527, 31160754, 21776002, 31980526, 32747562, 33096615, 29062245, 30030956, 30487145, 31346875, 31195736, 29907799, 30344259, 31541171, 30275481, 33105617)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Athena Diagnostics, SCV000841702.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (15)

Description

This variant is expected to severely impact normal RNA splicing, and consequently, protein structure and/or function. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). The variant is a common founder originating from Eastern Siberia (PMID: 21776002). This variant is also referred to as IVS1+1G>A, -3170G>A, -3201G>A, -3179G>A, or -3172G>A in published literature. Assessment of experimental evidence suggests this variant results in abnormal protein function. RNA studies performed on patient lymphocytes yielded no detectable transcript (PMID: 11935342). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV000957075.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

This sequence change falls in intron 1 of the GJB2 gene. It does not directly change the encoded amino acid sequence of the GJB2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs80338940, gnomAD 0.03%). This variant has been observed in individual(s) with deafness (PMID: 10218527, 11935342, 21776002, 24840842, 24959830, 27481527, 27843504). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Yakut ancestry (PMID: 21776002). ClinVar contains an entry for this variant (Variation ID: 17029). Studies have shown that this variant alters GJB2 gene expression (PMID: 11935342). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001156573.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The GJB2 c.-23+1G>A variant (rs80338940), also known as IVS-1+1G>A, has been reported in individuals with autosomal recessive deafness (Barashkov 2011, Denoyelle 1999, Shahin 2002). Functional characterization of the variant indicates an absence of detectable transcript in the patient (Shahin 2002). The variant is listed as pathogenic in ClinVar (Variation ID: 17029), and observed 5 times in the Genome Aggregation Database general population database (5/30850 alleles). The variant is located in the splice consensus site, and computational algorithms (GeneSplicer, Human Splicing Finder, MaxEntScan, MutationTaster, NetGene2, NNSplice, SpliceSiteFinder-like) predict the loss of the canonical splice donor. Based on the above information, the variant is classified as pathogenic. References: Barashkov N et al. Autosomal recessive deafness 1A (DFNB1A) in Yakut population isolate in Eastern Siberia: extensive accumulation of the splice site mutation IVS1+1G>A in GJB2 gene as a result of founder effect. J Hum Genet. 2011; 56(9):631-9. Denoyelle F et al. Clinical features of the prevalent form of childhood deafness, DFNB1, due to a connexin-26 gene defect: implications for genetic counselling. Lancet. 1999; 353(9161):1298-303. Shahin H et al. Genetics of congenital deafness in the Palestinian population: multiple connexin 26 alleles with shared origins in the Middle East. Hum Genet. 2002; 110(3):284-9.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV001245656.21

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001905675.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		not provided	not provided	not provided	not provided

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001951168.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001975771.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002024266.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 26, 2024

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