13-20189346-AG-A

Position:

• chr13-20189346-AG-A

Variant summary

Our verdict is Pathogenic. Variant got 8 ACMG points: 12P and 4B. BS1 PVS1 PM3 PS3_Moderate

This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA127025/MONDO:0019497/005

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: GJB2 NM_004004.6 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:33 O:1
• Conservation: PhyloP100: 6.77

Genes affected

GJB2 (HGNC:4284): (gap junction protein beta 2) This gene encodes a member of the gap junction protein family. The gap junctions were first characterized by electron microscopy as regionally specialized structures on plasma membranes of contacting adherent cells. These structures were shown to consist of cell-to-cell channels that facilitate the transfer of ions and small molecules between cells. The gap junction proteins, also known as connexins, purified from fractions of enriched gap junctions from different tissues differ. According to sequence similarities at the nucleotide and amino acid levels, the gap junction proteins are divided into two categories, alpha and beta. Mutations in this gene are responsible for as much as 50% of pre-lingual, recessive deafness. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Pathogenic. Variant got 8 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB2	NM_004004.6	c.235del	p.Leu79CysfsTer3	frameshift_variant	2/2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3	c.235del	p.Leu79CysfsTer3	frameshift_variant	2/2		XP_011533351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5	c.235del	p.Leu79CysfsTer3	frameshift_variant	2/2	1	NM_004004.6	ENSP00000372299	P1
GJB2	ENST00000382844.2	c.235del	p.Leu79CysfsTer3	frameshift_variant	1/1			ENSP00000372295	P1

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00866

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000469 AC: 118 AN: 251392 Hom.: 0 AF XY: 0.000434 AC XY: 59 AN XY: 135884

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00620

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000180 AC: 263 AN: 1461826 Hom.: 0 Cov.: 33 AF XY: 0.000182 AC XY: 132 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00640

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152314 Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25 AN XY: 74494

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00868

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000217 Hom.: 0

Bravo AF: 0.000272

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:33 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:15 Other:1

Pathogenic, no assertion criteria provided	case-control	Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	Feb 26, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 10, 2016	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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, flagged submission	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Jan 25, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Aug 29, 2017	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. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 20, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Integrating Genomics into Medicine, Frazer Institute, University Of Queensland	Jun 02, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Center for Molecular Medicine, Children’s Hospital of Fudan University	Mar 08, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	May 09, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Sep 20, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Apr 19, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Henan Neurodevelopment Engineering Research Center for Children, Children's Hospital Affiliated to Zhengzhou University	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 20, 2019	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 16, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 13, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Dec 17, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 18, 2019	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 21, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 10, 2023	- -

Hearing loss Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Mar 20, 2015

- -

Autosomal recessive nonsyndromic hearing loss 1A;C2675750:Autosomal dominant nonsyndromic hearing loss 3A Pathogenic:1

Pathogenic, criteria provided, single submitter

reference population

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Mar 18, 2016

- -

Nonsyndromic genetic hearing loss Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Sep 14, 2018

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. -

GJB2-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 24, 2024

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. -

Autism spectrum disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Gene Friend Way, National Innovation Center

Jul 28, 2023

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. -

Autosomal dominant nonsyndromic hearing loss 3A Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Mar 08, 2016

- -

Autosomal recessive nonsyndromic hearing loss 1A;C2675235:Autosomal recessive nonsyndromic hearing loss 1B Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

Deafness, digenic, GJB2/GJB3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2009

- -

Hearing impairment Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Autosomal dominant keratitis-ichthyosis-hearing loss syndrome;C0265964:Mutilating keratoderma;C0266004:Knuckle pads, deafness AND leukonychia syndrome;C1835672:Palmoplantar keratoderma-deafness syndrome;C1844678:X-linked mixed hearing loss with perilymphatic gusher;C1865234:Ichthyosis, hystrix-like, with hearing loss;C2673759:Autosomal recessive nonsyndromic hearing loss 1A;C2675750:Autosomal dominant nonsyndromic hearing loss 3A Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 11, 2022

- -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 10, 2012

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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80338943; hg19: chr13-20763485;