rs111033253

Positions:

• chr13-20189255-CCCCTTGATGAACTT-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_004004.6(GJB2):​c.313_326del​(p.Lys105GlyfsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000179 in 1,613,512 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (1 hom.)
• Consequence: GJB2 NM_004004.6 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:28
• Conservation: PhyloP100: 3.16

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 16 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 27 pathogenic variants in the truncated region.
• PP5: Variant 13-20189255-CCCCTTGATGAACTT-C is Pathogenic according to our data. Variant chr13-20189255-CCCCTTGATGAACTT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 44737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-20189255-CCCCTTGATGAACTT-C is described in Lovd as [Pathogenic]. Variant chr13-20189255-CCCCTTGATGAACTT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB2	NM_004004.6	c.313_326del	p.Lys105GlyfsTer5	frameshift_variant	2/2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3	c.313_326del	p.Lys105GlyfsTer5	frameshift_variant	2/2		XP_011533351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5	c.313_326del	p.Lys105GlyfsTer5	frameshift_variant	2/2	1	NM_004004.6	ENSP00000372299	P1
GJB2	ENST00000382844.2	c.313_326del	p.Lys105GlyfsTer5	frameshift_variant	1/1			ENSP00000372295	P1

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000132 AC: 33 AN: 250302 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135372

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.0000474

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000182 AC: 266 AN: 1461346 Hom.: 1 AF XY: 0.000193 AC XY: 140 AN XY: 726976

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.0000378

Gnomad4 NFE exome AF: 0.000210

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74336

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000182 Hom.: 0

Bravo AF: 0.000132

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:28

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:11

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 26, 2019	NM_004004.5(GJB2):c.313_326del14(K105Gfs*5) is classified as pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. Sources cited for classification include the following: PMID 22567152. Classification of NM_004004.5(GJB2):c.313_326del14(K105Gfs*5) 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	Illumina Laboratory Services, Illumina	Aug 15, 2018	The GJB2 c.313_326delAAGTTCATCAAGGG (p.Lys105GlyfsTer5) variant results in a frameshift and is predicted to result in premature termination of the protein. Across a selection of the available literature, the p.Lys105GlyfsTer5 variant has been identified in a total of 59 individuals with autosomal recessive nonsyndromic hearing loss including 18 homozygotes and 41 compound heterozygotes (Denoyelle et al. 1999; Marlin et al. 2005; Bazazzadegan et al 2012; Mikstiene et al. 2016). Thirty-seven of the compound heterozygotes carry c.35delG, a well known pathogenic variant, on the second allele. The p.Lys105GlyfsTer5 variant was found in a heterozygous state in two control individuals and is reported at a frequency of 0.00032 in the South Asian population of the Genome Aggregation Database. Based on the collective evidence and potential impact of frameshift variants, the p.Lys105GlyfsTer5 variant is classified as pathogenic for autosomal recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 18, 2016	Variant summary: The GJB2 c.313_326delAAGTTCATCAAGGG (p.Lys105Glyfs) variant (alternatively also known as 313del14, 313-326del14, or 312del14) results in a premature termination codon, predicted to cause a truncated or absent GJB2 protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. If NMD is escaped, this variant is expected to truncate gap junction protein, cysteine-rich domain and connexin, N-terminal domain (InterPro).Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Gln124X, p.Gln164X, c.647_650delGAGA, etc.). This variant was found in 12/121692 control chromosomes at a frequency of 0.0000986, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). This variant is recurrently reported in patients with autosomal recessive NSHL and is reported to have hearing loss less severe than the c.35delG homozygotes (Kupka_2002, Wu_2002, Cryns_2004, Marlin_2005). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Dec 09, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genomics Laboratory, Stanford Medicine	Jun 24, 2021	The p.Lys105Glyfs*5 variant in the GJB2 gene is a well reported cause of nonsyndromic hearing loss. This variant was determined to be in trans with other pathogenic variants (p.Gly12Valfs*2, p.Met34Thr), consistent with autosomal recessive inheritance (Marlin et al., 2005; Mikstiene et al., 2016). The presence of this variant with an established disease-causing variant on the opposite allele increases suspicion for its pathogenicity. The p.Lys105Glyfs*5 variant has also been identified in 9/30,614 South Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant results in a 14 bp deletion, which causes a shift in the protein reading frame, leading to a premature termination codon 5 amino acids downstream. Loss of function is an established mechanism of disease for the GJB2 gene. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Lys105Glyfs*5 variant as pathogenic for autosomal recessive nonsyndromic hearing loss based on the information above. [ACMG evidence codes used: PVS1; PM3_verystrong; PM2_supporting] -
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	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Apr 12, 2021	ACMG codes:PVS1, PM2, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 23, 2024	Criteria applied: PVS1,PM3_VSTR -

not provided Pathogenic:10

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.Lys105Glyfs*5) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 122 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs111033253, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with autosomal recessive deafness (PMID: 10218527, 22567152, 26896187, 27224056). ClinVar contains an entry for this variant (Variation ID: 44737). This variant disrupts the p.Pro173, p.Arg184 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10874298, 10982180, 15855033, 25708704). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 26, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	GJB2: PM3:Very Strong, PVS1, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jan 13, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 20, 2020	This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. 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	Feb 03, 2022	The GJB2 c.313_326del; p.Lys105GlyfsTer5 variant (rs111033253) is reported in the literature in individuals affected with hearing loss, both in the homozygous state and in trans to other pathogenic variants (Dalamon 2013, Denoyelle 1999, Kupa 2002, Mikstiene 2016). This variant is reported as pathogenic by numerous laboratories in ClinVar (Variation ID: 44737) and it is found in the general population with an overall allele frequency of 0.01% (38/281690 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting 14 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, the c.313_326del variant is considered to be pathogenic. References: Dalamon V et al. Identification of four novel connexin 26 mutations in non-syndromic deaf patients: genotype-phenotype analysis in moderate cases. Mol Biol Rep. 2013 Dec;40(12):6945-55. PMID: 24158611. 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 Apr 17;353(9161):1298-303. PMID: 10218527. Kupka S et al. Frequencies of GJB2 mutations in German control individuals and patients showing sporadic non-syndromic hearing impairment. Hum Mutat. 2002 Jul;20(1):77-8. PMID: 12112666. Mikstiene V et al. The high frequency of GJB2 gene mutation c.313_326del14 suggests its possible origin in ancestors of Lithuanian population. BMC Genet. 2016 Feb 19;17:45. PMID: 26896187. -
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	Mayo Clinic Laboratories, Mayo Clinic	Aug 31, 2022	PM2_supporting, PM3_very_strong, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 11, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 19, 2021	Frameshift variant predicted to result in protein truncation, as the last 122 amino acids are lost and replaced with 4 incorrect amino acids (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 22975760, 30094485, 10218527, 27224056, 25999548, 22567152, 29701678, 30168495, 30344259, 9529365, 29625052, 31980526, 31160754, 33096615, 31589614, 32067424, 26896187) -

Hearing impairment Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 13, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	Apr 12, 2021	PVS1_Strong, PM2_Moderate, PM3_Moderate -

Hearing loss Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

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

Nov 13, 2014

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Nonsyndromic genetic hearing loss Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

INGEBI, INGEBI / CONICET

Aug 21, 2020

Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the filtering allele frequency of the c.313_326del (p.Lys105fs*5) variant in the GJB2 gene is 0,015% (9/30614 South Asian alleles with 95% CI) in Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which meets the PM2_Supporting criteria. The c.313_326del variant is predicted to cause a premature stop codon in the only exon of GJB2 that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism (PVS1). This variant has been detected in trans with at least 4 pathogenic variants in different hearing loss patients (PMID: 10218527, 10982180, 11551103, 24158611, 27224056) applying to PM3_VeryStrong. This variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss: PM2_Supporting, PVS1, PM3_VeryStrong. -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 04, 2017

The p.Lys105fs variant in GJB2 is a well-known pathogenic variant and has been i dentified in many individuals with hearing loss who were homozygous or compound heterozygous with another pathogenic variant in GJB2 (Marlin 2005). It has been reported in 27/126134 European chromosomes and 10/20780 South Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/; dbSNP rs1 99976861). This frequency in the general population is consistent with the carri er frequency for autosomal recessive hearing loss. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 105 and leads to a premature termination codon 5 amino acids downstream . In summary, this variant meets criteria to be classified as pathogenic for aut osomal recessive hearing loss based on the predicted impact to the protein and m ultiple previously reported affected compound heterozygotes. ACMG/AMP Criteria a pplied: PVS1, PM3_VeryStrong. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs111033253; hg19: chr13-20763394;