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

gnomAD frequency: 0.00017  dbSNP: rs80338940

Total submissions: 39

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211766	SCV000061468	pathogenic	Rare genetic deafness	2022-06-30	criteria provided, single submitter	clinical testing	The c.-23+1G>A variant in GJB2 has been reported in many probands with hearing loss (Denoyelle 1999 PMID: 10218527, Shahin 2002 PMID: 11935342, Sirmaci 2006 PMID: 17406097, Yuan 2010 PMID: 21122151, Barashkov 2011 PMID: 21776002). Most of these probands were homozygous or compound heterozygous. In addition, functional studies have shown that this variant disrupts splicing, yielding no detectable mRNA (Shahin 2002 PMID: 11935342). In summary, this variant meets our criteria to be classified as pathogenic. ACMG/AMP Criteria applied: PM3_VeryStrong; PS3.
Genetic Services Laboratory, University of Chicago	RCV000146002	SCV000193153	pathogenic	Hearing impairment	2013-02-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000418755	SCV000516861	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing	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)
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000018557	SCV000599720	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2017-05-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000018557	SCV000698237	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2016-10-24	criteria provided, single submitter	clinical testing	Variant summary: The GJB2 c.-23+1G>A variant (alternatively also known as IVS1+1G>A, -3170G>A, -3201G>A, -3179G>A, and -3172G>A) involves the alteration of the invariant splice donor site in intron 1. 5/5 splice prediction tools predict that this variant eliminates the 5' splicing donor site. The prediction result was confirmed by a functional study; RNA isolated from lymphocytes from the proband carrying c.-23-1G>A variant and subsequent sequencing of cDNA showed no transcript from this allele (Shahin_2002). This variant was found in 21/4256 control chromosomes at a frequency of 0.0049342, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). This variant has been reported as one of the common pathogenic variants causing ARNSHL in literature with consistent genotype-phenotype data. The variant has also been postulated to originate from and to have a founder effect in central Asia (Barashkov_2011). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Athena Diagnostics	RCV000418755	SCV000841702	pathogenic	not provided	2022-03-23	criteria provided, single submitter	clinical testing	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.
Fulgent Genetics, Fulgent Genetics	RCV000762908	SCV000893318	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A; Mutilating keratoderma; Ichthyosis, hystrix-like, with hearing loss; Autosomal dominant keratitis-ichthyosis-hearing loss syndrome; Palmoplantar keratoderma-deafness syndrome; Knuckle pads, deafness AND leukonychia syndrome; Autosomal dominant nonsyndromic hearing loss 3A; X-linked mixed hearing loss with perilymphatic gusher	2021-07-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000418755	SCV000957075	pathogenic	not provided	2024-01-31	criteria provided, single submitter	clinical testing	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000418755	SCV001156573	pathogenic	not provided	2021-02-12	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV001004401	SCV001163373	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A; Autosomal recessive nonsyndromic hearing loss 1B		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000018557	SCV001194242	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2019-12-24	criteria provided, single submitter	clinical testing	NM_004004.5(GJB2):c.-23+1G>A is classified as pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. Sources cited for classification include the following: PMID 21776002. Classification of NM_004004.5(GJB2):c.-23+1G>A is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Center for Human Genetics Tuebingen	RCV000418755	SCV001245656	pathogenic	not provided	2017-08-01	criteria provided, single submitter	clinical testing
INGEBI, INGEBI / CONICET	RCV001257033	SCV001433538	pathogenic	Nonsyndromic genetic hearing loss	2020-08-21	criteria provided, single submitter	clinical testing	Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the c.-23+1G>A variant in GJB2 gene is absent from population databases (gnomAD, GO-ESP, 1000 genomes) meeting PM2 criteria. This type of variant is predicted to generate a loss of the donor splicing site in GJB2 gene , which is a known mechanism of disease (PVS1). The c.-23+1G>A variant has been identified in trans with at least 4 pathogenic variants in hearing loss patients applying to PM3_VeryStrong rule (PMID: 10218527, 11313763, 16380907). It was demonstrated that this genetic variant disrupted splicing, yielding no detectable message by sequencing the cDNA from lymphoblastoid cell line of J3 from mutant allele, meeting PS3_Supporting criteria (PMID: 11935342). Therefore, the c.23-23+1G>A variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss (PM2, PVS1, PM3_VerySrong, PS3_Supporting)
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	RCV000146002	SCV001571780	pathogenic	Hearing impairment	2021-04-12	criteria provided, single submitter	clinical testing	PVS1_Strong, PS1_Strong, PM3_Moderate, BP4_Supporting
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001813995	SCV001755100	pathogenic	Ear malformation	2021-07-10	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000418755	SCV001905675	pathogenic	not provided	2021-09-15	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000418755	SCV002024266	pathogenic	not provided	2023-12-21	criteria provided, single submitter	clinical testing
King Laboratory, University of Washington	RCV000018557	SCV002059940	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2020-08-01	criteria provided, single submitter	research	GJB2 c.-23+1G>A is homozygous in a Palestinian child with severe to profound hearing loss (Abu Rayyan 2020). Based on analysis of RNA from the patient, no transcript from the mutant allele was detectable (PMID: 11935342). The variant is not present in 1300 Palestinian controls and absent from gnomAD v2.1.1.
MGZ Medical Genetics Center	RCV000018557	SCV002581008	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2022-07-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003147300	SCV003836380	pathogenic	Autosomal dominant nonsyndromic hearing loss 3A	2022-03-23	criteria provided, single submitter	clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000018557	SCV003922400	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2023-04-28	criteria provided, single submitter	clinical testing	A heterozygous 5’ splice site variant in intron 1 of the GJB2 gene that affects the invariant GT donor splice site downstream of exon 1 was detected. This variant has not been reported in the 1000 genomes and gnomdAD (v2) databases and has a minor allele frequency of 0.03% and 0.02% in the gnomAD (v3.1) and topmed databases, respectively. The in silico prediction of the variant is damaging by MutationTaster2. The reference base is conserved across mammals. In summary, the variant meets our criteria to be classified as likely pathogenic.
Lifecell International Pvt. Ltd	RCV003147300	SCV003926486	pathogenic	Autosomal dominant nonsyndromic hearing loss 3A		criteria provided, single submitter	clinical testing	A Heterozygous Splice site donor variant c.-23+1G>A in Exon 1 of the GJB2 gene that results in the amino acid substitution was identified. The observed variant has a maximum allele frequency is novel in gnomAD exomes and 0.00019% in genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic [Variation ID: 17029]. The literature have been suggesting that, heterozygosity for a GJB2 or GJB6 mutation connotes carrier status for NSHL and rarely can cause autosomal dominant hearing loss by Vassos Neocleous et al., 2014. For these reasons, this variant has been classified as Pathogenic.
Johns Hopkins Genomics, Johns Hopkins University	RCV000018557	SCV003927247	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2023-04-28	criteria provided, single submitter	clinical testing	This GJB2 canonical splice variant has been reported in the homozygous or compound heterozygous state in multiple unrelated individuals with autosomal recessive deafness 1A. This variant (rs80338940) is present in a large population dataset (gnomAD v3.1.2: 42/152092 total alleles; 0.03%; no homozygotes), and has been reported in ClinVar (Variation ID 17029). The variant destroys a canonical splice donor site, is predicted to cause abnormal gene splicing and has supporting functional evidence1. We consider c.-23+1G>A in GJB2 to be pathogenic.
Integrating Genomics into Medicine, Frazer Institute, University Of Queensland	RCV000018557	SCV003935291	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2023-06-02	criteria provided, single submitter	clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000018557	SCV003936065	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2023-04-04	criteria provided, single submitter	clinical testing	A heterozygous 5’ splice site variant in intron 1 of the GJB2 gene that affects the invariant GT donor splice site downstream of exon 1 (c.-23+1G>A; ENST00000382848.5) was detected. The observed variant has previously been reported (as IVS1+1G>A) in patients affected with hearing loss [PMID: 27843504, ClinVar: VCV000017029.72]. This variant has not been reported in the 1000 genomes and gnomdAD (v2) databases and has a minor allele frequency of 0.03% and 0.02% in the gnomAD (v3.1) and topmed databases, respectively. The in-silico prediction of the variant is damaging by MutationTaster2. The reference base is conserved across mammals. In summary, the variant meets our criteria to be classified as likely pathogenic.
Institute of Human Genetics, University Hospital of Duesseldorf	RCV003458323	SCV004177271	pathogenic	Autosomal recessive nonsyndromic hearing loss 104		criteria provided, single submitter	not provided
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000018557	SCV004806709	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2024-03-26	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000418755	SCV005090001	pathogenic	not provided	2024-07-31	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000018557	SCV005400136	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2024-10-10	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with both deafness and skin conditions (OMIM). Dominant negative is also a suggested mechanism (PMID: 28428247). (I) 0108 - This gene is associated with both recessive and dominant disease. The autosomal dominant diseases are commonly associated with pathogenic missense variants. The autosomal recessive disease is associated with biallelic loss of function variants and includes missense and protein truncating variants (NIH Genetics Home Reference, PMID: 12792423). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 31160754). (I) 0115 - Variants in this gene are known to have variable expressivity. Severity can range from mild to profound with intrafamilial variability also commonly seen. Commonly, truncating variants are associated to a more severe hearing loss (PMID: 20301449). (I) 0211 - Canonical splice site variant without proven consequence on splicing. RNA RT-PCR performed on an affected individual’s lymphocytes who is compound heterozygous for this variant and c.35delG showed the deletion variant was present, however, the splicing effect of c.-23+1G>A was deemed to be inconclusive (PMID: 11935342). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (34 heterozygotes, 0 homozygotes). (SP) 0311 - An alternative nucleotide change at the same canonical splice site is present in gnomAD (v3) at a frequency of 0.000006 (1 heterozygote, 0 homozygote). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant is a well-reported pathogenic variant and has been postulated to have a founder effect in deaf individuals from South Siberian populations (ClinVar, Deafness Variation database, PMID: 37239361, PMID: 32708339). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000018557	SCV000038839	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2011-09-01	no assertion criteria provided	literature only
GeneReviews	RCV000018557	SCV000041037	pathologic	Autosomal recessive nonsyndromic hearing loss 1A	2011-07-14	no assertion criteria provided	literature only	Converted during submission to Pathogenic.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000018557	SCV000223931	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2015-02-11	no assertion criteria provided	clinical testing
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678858	SCV000805051	pathogenic	Hearing loss	2017-08-14	no assertion criteria provided	clinical testing
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	RCV000018557	SCV000902315	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2019-02-26	no assertion criteria provided	case-control
Natera, Inc.	RCV000018557	SCV001455338	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2020-09-16	no assertion criteria provided	clinical testing
University of Washington Center for Mendelian Genomics, University of Washington	RCV001291328	SCV001479801	likely pathogenic	Hearing loss, autosomal recessive		no assertion criteria provided	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000418755	SCV001951168	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000418755	SCV001975771	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532386	SCV004103054	pathogenic	GJB2-related disorder	2024-05-01	no assertion criteria provided	clinical testing	The GJB2 c.-23+1G>A variant is located in the 5' untranslated region. This variant is also described as c.-3170G>A or IVS1+1G>A and has been reported to be causative for autosomal recessive nonsyndromic hearing loss (Denoyelle et al. 1999. PubMed ID: 10218527; Barashkov et al. 2011. PubMed ID: 21776002; Barashkov et al. 2014. PubMed ID: 24959830). This variant is reported in 0.032% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is listed as pathogenic in ClinVar by multiple laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/17029/). This variant is interpreted as pathogenic.