Submissions for variant NM_004004.6(GJB2):c.235del (p.Leu79fs)

dbSNP: rs80338943

Total submissions: 34

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV000211768	SCV000840502	pathogenic	Nonsyndromic genetic hearing loss	2018-09-14	reviewed by expert panel	curation	The filtering allele frequency of the p.Leu79CysfsX3 variant in the GJB2 gene is 0.55% (121/ 18870) of East Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BS1). The ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for nonsyndromic hearing loss outweighs the high allele frequency of the variant in population databases. Therefore, the BS1 code will not contribute to the overall classification. The p.Leu79CysfsX3 variant in GJB2 is predicted to cause a premature stop codon in the only exon of the gene, leading to absent protein in a gene in which loss-of-function is an established mechanism (PVS1). This variant has been detected in patients with hearing loss in trans with at least 4 pathogenic or suspected-pathogenic variants (PM3_VS; PMID: 10983956, 10633133). A dye transfer assay, a functional study, has shown that the variant impacts protein function (PS3_M; PMID: 12352684). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PVS1, PM3_VS, PS3_M, BS1.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000844630	SCV000061489	pathogenic	Rare genetic deafness	2012-02-10	criteria provided, single submitter	clinical testing	The c.235delC variant in GJB2 is a well-studied pathogenic variant (Abe 2000, Pa rk 2000, Choung 2002, Liu 2002, Ohtsuka 2003, Yao 2012). This variant is predict ed to cause a frameshift, which alters the protein's amino acid sequence beginni ng at codon 79 and leads to a premature termination codon 3 amino acids downstre am. This alteration is then predicted to lead to a truncated or absent protein. In summary, this variant meets criteria to be classified as pathogenic for heari ng loss in an autosomal recessive manner. ACMG/AMP Criteria applied: PVS1, PM3_ VeryStrong.
Genetic Services Laboratory, University of Chicago	RCV000146011	SCV000193162	pathogenic	Hearing impairment	2013-02-08	criteria provided, single submitter	clinical testing
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000490501	SCV000267340	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A; Autosomal dominant nonsyndromic hearing loss 3A	2016-03-18	criteria provided, single submitter	reference population
GeneDx	RCV000255303	SCV000322427	pathogenic	not provided	2019-11-18	criteria provided, single submitter	clinical testing	One of the most common variants reported in the GJB2 gene, with a carrier frequency of 1-2% in the Japanese and Chinese populations (Fuse et al., 1999; Dzhemileva et al., 2010; Yao et al., 2012); Frameshift variant predicted to result in protein truncation, as the last 148 amino acids are lost and replaced with 2 incorrect amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Published functional studies demonstrate a damaging effect; cells expressing c.235delC fail to reach their destination in the cell membrane and have reduced gap junction activity (Choung et al., 2002; Zhang et al., 2010); Classified as pathogenic by the ClinGen Hearing Loss Expert Panel (SCV000840502.3; Oza et al., 2018); This variant is associated with the following publications: (PMID: 12505163, 26336802, 25266519, 26119842, 30275481, 20095872, 25262649, 22975760, 12352684, 23469187, 24945352, 22088281, 15479191, 22747691, 20739944, 17666888, 10501520, 19043807, 26061264, 26763877, 27308839, 27045574, 28012523, 16952406, 12111646, 12169891, 30282152, 29447821, 30589569, 29086887, 29771057, 30693673, 31195736, 30816908, 30036422, 30146550, 31370293, 30733538, 31347505, 31162818, 30344259, 31564438, 29625052, 31914302, 26689913, 31541171, 31827275, 31980526, 31160754, 30896630, 32747562, 22875492, 31589614, 29871260, 32973888, 32708339)
Counsyl	RCV000410166	SCV000487398	pathogenic	Autosomal dominant nonsyndromic hearing loss 3A	2016-03-08	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000018538	SCV000599737	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2017-05-09	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000255303	SCV000603827	pathogenic	not provided	2023-03-13	criteria provided, single submitter	clinical testing	The GJB2 c.235del; p.Leu79CysfsTer3 variant (rs80338943) is a well-studied variant associated with autosomal recessive nonsyndromic hearing loss (Choung 2002, Du 2016, Fuse 1999, Han 2008, Zhang 2010). This variant is reported in ClinVar (Variation ID: 17014) and is found in the general population with an overall allele frequency of 0.047% (134/282,792 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Choung YH et al. Functional study of GJB2 in hereditary hearing loss. Laryngoscope. 2002 Sep;112(9):1667-71. PMID: 12352684. Du Y et al. Analysis of p.V37I compound heterozygous mutations in the GJB2 gene in Chinese infants and young children. Biosci Trends. 2016 Jul 19;10(3):220-6. PMID: 27350192. Fuse Y et al. Three novel connexin26 gene mutations in autosomal recessive non-syndromic deafness. Neuroreport. 1999 Jun 23;10(9):1853-7. PMID: 10501520. Han SH et al. Carrier frequency of GJB2 (connexin-26) mutations causing inherited deafness in the Korean population. J Hum Genet. 2008;53(11-12):1022-8. PMID: 19043807. Zhang Y et al. Three common GJB2 mutations causing nonsyndromic hearing loss in Chinese populations are retained in the endoplasmic reticulum. Acta Otolaryngol. 2010 Jul;130(7):799-803. PMID: 20095872.
Athena Diagnostics	RCV000255303	SCV000613508	pathogenic	not provided	2023-01-16	criteria provided, single submitter	clinical testing	This variant is expected to result in the loss of a functional protein. This variant is one of the most common variants associated with autosomal recessive form of nonsyndromic hearing loss (PMID: 17505205, 19043807, 15700112), therefore the frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant appears to segregate with disease in at least one family. Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiments show this variant impairs gap junction channel activity (PMID: 12352684, 12505163). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000018538	SCV000698238	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2016-05-10	criteria provided, single submitter	clinical testing	Variant summary: The GJB2 c.235delC (p.Leu79Cysfs) variant results in a premature termination codon, predicted to cause a truncated or absent GJB2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Mutation taster predicts a damaging outcome for this variant. It was found in 44/121376 control chromosomes at a frequency of 0.0003625, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). The variant was reported in several autosomal recessive non-syndromic hearing loss patients either in homozygosity or in compound heterozygosity with other pathogenic GJB2 variants indicating pathogenicity. Additionally, a functional study demonstrated the variant to result in a truncated form of GJB2 which is not capable to facilitate junctional conductance, further supporting a deleterious impact. Moreover, multiple clinical diagnostic laboratories classified this variant as Pathogenic. Taken together, this variant is classified as pathogenic.
Eurofins Ntd Llc (ga)	RCV000255303	SCV000700278	pathogenic	not provided	2017-12-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000255303	SCV000938184	pathogenic	not provided	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu79Cysfs*3) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 148 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs80338943, gnomAD 0.6%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individuals with autosomal recessive non-syndromic hearing loss (PMID: 10501520, 15479191, 17505205, 20739944, 22747691, 25266519, 26061264, 27045574). It is commonly reported in individuals of East Asian ancestry (PMID: 14505035). This variant is also known as c.233delC. ClinVar contains an entry for this variant (Variation ID: 17014). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects GJB2 function (PMID: 12352684, 20095872). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001004392	SCV001163364	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A; Autosomal recessive nonsyndromic hearing loss 1B		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000018538	SCV001193830	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2019-12-20	criteria provided, single submitter	clinical testing	NM_004004.5(GJB2):c.235delC(aka L79Cfs*3) is classified as pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. Sources cited for classification include the following: 12505163, 20095872, 20497192, 16380907, and 15937416. Classification of NM_004004.5(GJB2):c.235delC(aka L79Cfs*3) is based on the following criteria: The variant causes a premature termination codon that is not expected to be targeted by nonsense-mediated mRNA decay; however, literature evidence strongly supports pathogenicity. Please note: this variant was assessed in the context of healthy population screening.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000018538	SCV001244782	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2017-08-29	criteria provided, single submitter	clinical testing	A homozygous deletion variant was identified, NM_004004.5(GJB2):c.235delC in exon 2 of the GJB2 gene.This variant is predicted to create a frameshift from amino acid position 79 and introduce a stop codon three amino acids downstream, NP_003995.5(GJB2):p.(Leu79Cysfs*3) whichresults in loss of protein function through truncation (majority of the protein). Immunohistochemical analysis and functional studies have shown that this variant causes loss of targeting activity to the cell membrane and severe deterioration of gap junction activity (Choung, YH. et al. (2002)). This variant is present in the gnomAD population database at a frequency of 0.045% (125 in 277162, 0 homozygotes). It is a well studied variant and has been previously reported in patients with autosomal recessive deafness(Rabionet, R. et al. (2000), Yan, D. et al. (2003), ClinVar).Based on current information, this variant has been classified as PATHOGENIC.
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000018538	SCV001449024	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2016-04-19	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000018538	SCV001523116	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2019-03-20	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Revvity Omics, Revvity	RCV000255303	SCV002024253	pathogenic	not provided	2023-04-10	criteria provided, single submitter	clinical testing
3billion	RCV000018538	SCV002058528	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2022-01-03	criteria provided, single submitter	clinical testing	Frameshift: predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_S). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 12352684, PS3_M). The variant has been reported multiple times as an established pathogenic/likely pathogenic variant (ClinVar ID: VCV000017014, PMID:10501520, 3billion dataset). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000474, PM2_M). The same variant was previously reported several times in trans with another pathogenic variant in this gene (PMID: 10983956, 10633133, PM3_VS). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Centogene AG - the Rare Disease Company	RCV000018538	SCV002059531	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2019-09-20	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496402	SCV002809759	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	2022-04-11	criteria provided, single submitter	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000255303	SCV002818210	pathogenic	not provided	2022-12-17	criteria provided, single submitter	clinical testing
Integrating Genomics into Medicine, Frazer Institute, University Of Queensland	RCV000018538	SCV003935287	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2023-06-02	criteria provided, single submitter	clinical testing
Henan Neurodevelopment Engineering Research Center for Children, Children's Hospital Affiliated to Zhengzhou University	RCV000018538	SCV005374698	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A		criteria provided, single submitter	clinical testing
OMIM	RCV000018538	SCV000038820	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2009-02-01	no assertion criteria provided	literature only
OMIM	RCV000018539	SCV000038821	pathogenic	Deafness, digenic, GJB2/GJB3	2009-02-01	no assertion criteria provided	literature only
GeneReviews	RCV000018538	SCV000041042	not provided	Autosomal recessive nonsyndromic hearing loss 1A		no assertion provided	literature only
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678874	SCV000805067	pathogenic	Hearing loss	2015-03-20	no assertion criteria provided	clinical testing
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	RCV000018538	SCV000902316	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2019-02-26	no assertion criteria provided	case-control
Natera, Inc.	RCV000018538	SCV001453343	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2020-09-16	no assertion criteria provided	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000018538	SCV001984286	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2021-01-25	flagged submission	clinical testing
Center for Molecular Medicine, Children’s Hospital of Fudan University	RCV000018538	SCV002073944	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2022-03-08	no assertion criteria provided	clinical testing
Gene Friend Way, National Innovation Center	RCV003313925	SCV004013882	pathogenic	Autism spectrum disorder	2023-07-28	no assertion criteria provided	clinical testing	Among 16 children with non-syndromic sensorineural hearing loss and carried GJB2 mutations, 44% had additional disabilities, including specific learning disability, apraxia, epileptiform aphasia, attention deficit disorder, global developmental delay, and gross motor delay (PMID: 16154643). In our study, four children diagnosed with Autism Spectrum Disorder are carriers of this rs80338943 mutation.
PreventionGenetics, part of Exact Sciences	RCV004528121	SCV004110960	pathogenic	GJB2-related disorder	2024-07-24	no assertion criteria provided	clinical testing	The GJB2 c.235delC variant is predicted to result in a frameshift and premature protein termination (p.Leu79Cysfs*3). This variant has been reported to be causative for autosomal recessive non-syndromic hearing loss (Hwa et al. 2003. PubMed ID: 12792423; Chan et al. 2010. PubMed ID: 20154630; Pang et al. 2014. PubMed ID: 24945352; Xia et al. 2016. PubMed ID: 27045574). This variant is reported in 0.65% of alleles in individuals of East Asian descent in gnomAD. Frameshift variants in GJB2 are expected to be pathogenic. This variant is interpreted as pathogenic by the ClinGen Hearing Loss Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/17014/). We classify this variant as pathogenic.