rs80338942

chr13-20189414-CA-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 16P and 4B. PVS1 PP5_Very_Strong BS2

The NM_004004.6(GJB2):c.167del(p.Leu56ArgfsTer26) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000511 in 1,612,308 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. L56L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00050 (3 hom.)
• Consequence: GJB2 NM_004004.6 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:28 O:1
• Conservation: PhyloP100: 2.62

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 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 184 pathogenic variants in the truncated region.
• PP5: Variant 13-20189414-CA-C is Pathogenic according to our data. Variant chr13-20189414-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 17010.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-20189414-CA-C is described in Lovd as [Pathogenic]. Variant chr13-20189414-CA-C is described in Lovd as [Pathogenic].
• BS2: High Homozygotes in GnomAdExome at 3 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB2	NM_004004.6	c.167del	p.Leu56ArgfsTer26	frameshift_variant	2/2	ENST00000382848.5
GJB2	XM_011535049.3	c.167del	p.Leu56ArgfsTer26	frameshift_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB2	ENST00000382848.5	c.167del	p.Leu56ArgfsTer26	frameshift_variant	2/2	1	NM_004004.6	P1
GJB2	ENST00000382844.2	c.167del	p.Leu56ArgfsTer26	frameshift_variant	1/1			P1

Frequencies

GnomAD3 genomes AF: 0.000598 AC: 91 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000888 AC: 223 AN: 251070 Hom.: 3 AF XY: 0.000818 AC XY: 111 AN XY: 135666

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.0164

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000317

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.000502 AC: 733 AN: 1460102 Hom.: 3 Cov.: 33 AF XY: 0.000464 AC XY: 337 AN XY: 725966

Gnomad4 AFR exome AF: 0.0000898

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.0166

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000164

Gnomad4 OTH exome AF: 0.00149

GnomAD4 genome AF: 0.000598 AC: 91 AN: 152206 Hom.: 0 Cov.: 33 AF XY: 0.000578 AC XY: 43 AN XY: 74352

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.0187

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.000955

Alfa AF: 0.00174 Hom.: 0

Bravo AF: 0.000620

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000356

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:28 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:8 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Oct 18, 2019	NM_004004.5(GJB2):c.167delT(L56Rfs*26) is classified as pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. Please note that L56Rfs*26 is associated with a variable presentation, ranging from mild to profound hearing loss. Sources cited for classification include the following: PMID 24158611, 10049954, 16380907, 10596881, 11556849, 11074495, and 10982182. Classification of NM_004004.5(GJB2):c.167delT(L56Rfs*26) 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. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 19, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Apr 28, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 25, 2017	Variant summary: The c.167delT variant results in a premature termination codon, predicted to cause a truncated or absent GJB2 protein, which is a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.269dupT, c.313_326del, c.647_650delGATA, etc.). This variant was found in 84/123144 control chromosomes (3 homozygotes) at a frequency of 0.0006821, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). This variant is a well-known common pathogenic variant predominantly found in Ashkenazi Jewish population. In addition, multiple clinical laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant has been classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 02, 2020	Based on the classification scheme VCGS_Germline_v1.3.3, 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 autosomal recessive non syndromic hearing loss. However dominant negative is a likely mechanism for missense variants (PMID: 28428247). (I) 0108 - This gene is associated with both recessive and dominant disease. Truncating variants most likely to result in lost protein function are more commonly reported for recessive disease, while missense are more commonly reported for dominant disease (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. Two missense variants are most commonly reported with incomplete penetrance (PMID:31160754). (I) 0204 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with at least 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0305 - Variant is present in gnomAD v2 >=0.01 and <0.03 for a recessive condition (221 heterozygotes, 3 homozygotes). (I) 0701 - Other truncating variants downstream of the one identified in this case have very strong previous evidence for pathogenicity. Patients with these variants are generally reported with non syndromic autosomal recessive hearing loss (ClinVar, PMID: 26096904). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and has been reported in patients with autosomal recessive non syndromic hearing loss (ClinVar, PMID: 26096904) (SP) 1205 - This variant has been shown to be maternally inherited by trio analysis. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
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). The variant has been reported multiple times as an established pathogenic/likely pathogenic variant (ClinVar ID: VCV000017010, PMID:9285800). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000804, PM2_M). The same variant was previously reported several times in trans with another pathogenic variant in this gene (PMID: 24158611, 9285800, 24529908, 26096904, 17666888, PM3_VS). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	May 09, 2017	- -

not provided Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 05, 2019	Most individuals heterozygous for the c.167delT variant have normal hearing, although subclinical differences in the otoacoustic emissions of carriers has been noted upon audiologic examination (Morell et al., 1998); Frameshift variant predicted to result in protein truncation, as the last 171 amino acids are lost and replaced with 25 incorrect amino acids (Stenson et al., 2014); Classified as pathogenic by the ClinGen Hearing Loss Variant Curation Expert Panel (SCV000840535.3; Oza et al., 2018); Observed in 218/276720 (0.08%) alleles from individuals in large population cohorts, including 3 homozygous individuals (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27153395, 28702509, 22785241, 17666888, 24158611, 31160754, 25262649, 21465647, 22975760, 20739944, 11668644, 9819448, 26896187, 9285800, 26990548, 16380907, 15967879, 10982182, 23891399, 10903123, 20301449, 26096904, 24529908, 19125024, 15547683, 26236732, 11935342, 11386851, 29542069, 29984802, 27018795, 29431110, 11074495, 31370293, 31827275, 31980526, 32747562, 33096615, 31589614, 32067424) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 09, 2022	The GJB2 c.167delT; p.Leu56fs variant (rs80338942) creates a frameshift and is predicted to result in a truncated protein or absent transcript. Homozygous and compound heterozygous c.167delT variants have been reported in a number of patients with hearing loss (Kenna 2010, Snoeckx 2005). This variant is reported to ClinVar (Variation ID: 17010), and observed in the general population databases with an overall allele frequency of 0.08 percent (218/276720 alleles), including 3 homozygotes (Genome Aggregation Database). Importantly, this variant has been reported at a carrier frequency of 2.4-7.5 percent in Ashkenazi Jewish individuals (Bors 2004, Lerer 2000, Morell 1998, Sobe 1999). Taken together, this variant is considered pathogenic. REFERENCES Link to ClinVar database for c.167delT: https://www.ncbi.nlm.nih.gov/clinvar/variation/17010/ Bors A. et al. Frequencies of two common mutations (c.35delG and c.167delT) of the connexin 26 gene in different populations of Hungary. Int J Mol Med. 2004; 14(6):1105-1108. Gualandi F et al. Exploring the clinical and epidemiological complexity of GJB2-linked deafness. Am J Med Genet. 2002 Sep 15;112(1):38-45. Kenna MA et al. Audiologic Phenotype and Progression in GJB2 (Connexin 26) Hearing Loss. Arch Otolaryngol Head Neck Surg 2010; 136(1):81-87. Lerer I et al. Contribution of connexin 26 mutations in non-syndromic deafness in Ashkenazi patients and the variable phenotypic effect of the mutation 167delT. Am. J. Med. Genet. 2000; 95:53-56. Morell RJ et al. Mutations in the connexin 26 gene (GJB2) among Ashkenazi Jews with nonsyndromic recessive deafness. N Engl J Med. 1998; 339(21):1500-1505. Snoeckx RL et al. GJB2 Mutations and Degree of Hearing Loss: A Multicenter Study. Am J Hum Genet 2005; 77:945-957. Sobe T et al. High frequency of the deafness-associated 167delT mutation in the connexin 26 (GJB2) gene in Israeli Ashkenazim. Am J Med Genet. 1999; 86:499-500. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change creates a premature translational stop signal (p.Leu56Argfs*26) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 171 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs80338942, gnomAD 1.6%), 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 deafness (PMID: 15967879, 16380907, 21465647, 22695344, 24158611). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 9819448, 10982182, 11935342, 15967879, 16380907, 21465647, 22695344, 24158611). ClinVar contains an entry for this variant (Variation ID: 17010). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 21, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 24, 2022	This variant is expected to result in the loss of a functional protein. This variant is the most common pathogenic variant among the Ashkenazi Jewish population (PMID: 9819448), and therefore, the observed frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). In multiple individuals with nonsyndromic hearing loss, this variant has been seen with a single recessive pathogenic variant in the same gene. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 30, 2015	- -

Nonsyndromic genetic hearing loss Pathogenic:2

Pathogenic, reviewed by expert panel	curation	ClinGen Hearing Loss Variant Curation Expert Panel	Sep 19, 2018	The filtering allele frequency of the p.Leu56ArgfsX26 variant in the GJB2 gene is 1.4% (165/10106) of Ashkenazi Jewish 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 nonsyndromic hearing loss variants (BA1). 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 BA1 code will not contribute to the overall classification. The p.Leu56ArgfsX26 variant in GJB2 is predicted to cause a premature stop codon in the only coding exon of the gene, leading to an absent protein in a gene in which loss-of-function is an established disease 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: 24529908, 26096904, 24158611, 9285800, 17666888). 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, BA1. -
Pathogenic, criteria provided, single submitter	clinical testing	INGEBI, INGEBI / CONICET	Aug 31, 2020	Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: PVS1, PM3_VS -

Hearing loss Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

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

May 22, 2013

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 11, 2020

The alteration results in a premature stop codon: _x000D_ _x000D_ The c.167delT (p.L56Rfs*26) alteration, located in exon 2 (coding exon 1) of the GJB2 gene, results from a deletion of one nucleotide at position 167, causing a translational frameshift with a predicted alternate stop codon after 26 amino acids. Frameshifts are typically deleterious in nature; however, this frameshift occurs at the 3' terminus of GJB2, is not expected to trigger nonsense-mediated mRNA decay, and a truncated mutant protein could still be expressed (Maquat, 2004). This alteration impacts the last three-quarters of the protein. The alteration has been observed in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the GJB2 c.167delT alteration was observed in 0.08% (227/282466) of total alleles studied, with a frequency of 1.6% (168/10326) in the Ashkenazi Jewish subpopulation, including 3 homozygotes. The alteration has been observed in affected individuals: _x000D_ _x000D_ That alteration has been observed in conjunction with a second disease-causing allele in multiple individuals with non-syndromic hearing loss (Zelante, 1997; Morell, 1998; Dzhemileva, 2010; Mikstiene, 2016). Based on the available evidence, this alteration is classified as pathogenic. -

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

Pathogenic, no assertion criteria provided

research

Division of Human Genetics, Children's Hospital of Philadelphia

Jan 25, 2016

- -

Mutilating keratoderma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

Autosomal dominant nonsyndromic hearing loss 3A Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Dec 18, 2015

- -

GJB2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 16, 2018

The GJB2 c.167delT (p.Leu56ArgfsTer26) variant results in a frameshift and is predicted to result in premature truncation of the protein. The p.Leu56ArgfsTer26 variant is a well-known variant that is common in the Ashkenazi Jewish population, where the carrier rate is as high as 7.5% (Lerer et al. 2000). Across a selection of the available literature, the p.Leu56ArgfsTer26 variant has been identified in a total of 34 patients with autosomal recessive nonsyndromic hearing loss, including in 16 in a homozygous state, in 15 in a compound heterozygous state, and in three in a heterozygous state (Zelante et al. 1997; Morell et al. 1998; Lerer et al. 2000; Batissoco et al. 2009; Bonyadi et al. 2014; Amorini et al. 2015). The p.Leu56ArgfsTer26 variant was shown to segregate with disease in at least one family. Patients with this variant show a spectrum of phenotypic manifestation from mild to profound hearing loss, even among affected family members (Morell et al. 1998). Control data is unavailable for this variant, which is reported at a frequency of 0.00145 in the European-American population of the Exome Sequencing Project (Morell et al. 1998; Lerer et al. 2000). Based on the collective evidence and the potential impact of frameshift variants, the p.Leu56ArgfsTer26 variant is classified as pathogenic for GJB2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Dec 08, 2021

ACMG categories: PVS1,PM2,PP5 -

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

Feb 16, 2022

- -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 08, 2011

The c.167delT variant in GJB2 is known to be pathogenic with many supporting pub lications. 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: rs80338942; hg19: chr13-20763553;