rs111033253

Variant names:

• chr13-20189255-CCCCTTGATGAACTT-C
• rs111033253
• NM_004004.6:c.313_326delAAGTTCATCAAGGG

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_004004.6(GJB2):​c.313_326delAAGTTCATCAAGGG​(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. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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:37
• Conservation: PhyloP100: 3.16
• Publications: 26 publications found

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]

GJB2 Gene-Disease associations (from GenCC):

• Bart-Pumphrey syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• ichthyosis, hystrix-like, with hearing loss

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• keratoderma hereditarium mutilans

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P
• palmoplantar keratoderma-deafness syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
• autosomal recessive nonsyndromic hearing loss 1A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P, PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• autosomal dominant keratitis-ichthyosis-hearing loss syndrome

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics
• autosomal dominant nonsyndromic hearing loss 3A

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• KID syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000296095 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 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 105 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 44737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB2	NM_004004.6	c.313_326delAAGTTCATCAAGGG	p.Lys105GlyfsTer5	frameshift_variant	Exon 2 of 2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3	c.313_326delAAGTTCATCAAGGG	p.Lys105GlyfsTer5	frameshift_variant	Exon 2 of 2		XP_011533351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5	c.313_326delAAGTTCATCAAGGG	p.Lys105GlyfsTer5	frameshift_variant	Exon 2 of 2	1	NM_004004.6	ENSP00000372299.4
GJB2	ENST00000382844.2	c.313_326delAAGTTCATCAAGGG	p.Lys105GlyfsTer5	frameshift_variant	Exon 1 of 1	6		ENSP00000372295.1
ENSG00000296095	ENST00000736390.1	n.232-3689_232-3676delAAGTTCATCAAGGG		intron_variant	Intron 1 of 3

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

GnomAD2 exomes AF: 0.000132 AC: 33 AN: 250302 AF XY: 0.000118

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86258

European-Finnish (FIN) AF: 0.0000378 AC: 2 AN: 52882

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000210 AC: 234 AN: 1112006

Other (OTH) AF: 0.000166 AC: 10 AN: 60392

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

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000182 Hom.: 0

Bravo AF: 0.000132

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:37

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:14

May 01, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GJB2 c.313_326del14 (p.Lys105GlyfsX5) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00013 in 250302 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in GJB2 causing Autosomal Recessive Non-Syndromic Hearing Loss (0.00013 vs 0.025), allowing no conclusion about variant significance. c.313_326del14 has been observed in multiple individuals affected with Autosomal Recessive Non-Syndromic Hearing Loss (Wu_2002, Kupka_2002, Marlin_2005, Cryns_2004). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 14985372, 15967879, 12112666, 12172394). ClinVar contains an entry for this variant (Variation ID: 44737). Based on the evidence outlined above, the variant was classified as pathogenic.

Jul 23, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PVS1,PM3_VSTR

Jun 24, 2021

Clinical Genomics Laboratory, Stanford Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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]

Dec 09, 2021

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 09, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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 bi-allelic 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 (GeneReviews). (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) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (23 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant is a commonly reported pathogenic variant (ClinVar, Deafness Variation database), and has been reported in the literature in many individuals with hearing loss (PMIDs: 26896187, 27224056, 36579563). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Dec 26, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Aug 15, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

May 09, 2017

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 25, 2021

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Pathogenic

Review Status: flagged submission

Collection Method: clinical testing

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

A variant c.313_326del p.(Lys105GlyfsTer5) was observed in compound heterozygous state in GJB2 in proband. This variant is observed in heterozygous state in 289 individuals in gnomAD (v4.1.0) and two individuals in our in-house database. This variant is present in homozygous state in one individual in gnomAD (v4.1.0) and absent in our in-house database. Thus, the above-mentioned variant in compound heterozygous state in proband is the cause of the prelingual hearing loss in her.

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 12, 2021

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

ACMG codes:PVS1, PM2, PP5

Aug 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Jul 22, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed frameshift variant c.313_326delp.Lys105GlyfsTer5 in GJB2 gene has been reported previously in homozygous/compound heterozygous state in multiple individuals with autosomal recessive nonsyndromic hearing loss Mikstiene V, et al., 2016, Barashkov NA, et al., 2016. The p.Lys105GlyfsTer5 variant is reported with 0.01% allele frequency in gnomAD Exomes. It has been submitted to ClinVar as Likely Pathogenic/ Pathogenic multiple submissions. Other variants that disrupt this residue have been determined to be pathogenic and also this variant has been detected in trans with other pathogenic variants in different hearing loss patients Keivani A, et al., 2015. This variant causes a frameshift starting with codon Lysine 105, changes this amino acid to Glycine residue, and creates a premature Stop codon at position 5 of the new reading frame, denoted p.Lys105GlyfsTer5. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.

not provided Pathogenic:12

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 13, 2025

Centre for Clinical Genetics and Genomic Diagnostics, Zealand University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Compound heterozygous

Feb 11, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GJB2: PM3:Very Strong, PVS1:Strong, PM2

Mar 26, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 31, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_supporting, PM3_very_strong, PVS1

Jan 13, 2017

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Feb 03, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Dec 17, 2022

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 20, 2024

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population is consistent with pathogenicity. (http://gnomad.broadinstitute.org) This variant is not expected to cause loss of protein expression through nonsense-mediated decay. However, it disrupts a critical region of the protein, and therefore, is expected to severely disrupt its function. In multiple individuals with clinical features associated with autosomal recessive nonsyndromic hearing loss, this variant has been seen with a single recessive pathogenic variant in the same gene. In some published literature, this variant is referred to as c.312del14.

Oct 19, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:4

Mar 09, 2020

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 13, 2015

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 12, 2021

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1_Strong, PM2_Moderate, PM3_Moderate

Hearing loss Pathogenic:1

Nov 13, 2014

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Jun 18, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsyndromic genetic hearing loss Pathogenic:1

Aug 21, 2020

INGEBI, INGEBI / CONICET

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Monogenic hearing loss Pathogenic:1

Aug 06, 2025

Genetics Laboratory, Great Ormond Street Hospital NHS Foundation Trust, North Thames Genomic Laboratory Hub

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_supporting, PVS1_strong, PM3_very-strong

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

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Rare genetic deafness Pathogenic:1

May 04, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Mutilating keratoderma;C0266004:Knuckle pads, deafness AND leukonychia syndrome;C1835672:Palmoplantar keratoderma-deafness syndrome Pathogenic:1

Dec 31, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.2
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs111033253; hg19: chr13-20763394;