rs104894396

Positions:

• chr13-20189511-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 14P and 4B. BS1 PVS1 PM3 PS3

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the p.Trp24X variant in the GJB2 gene is 0.38% (137/ 30782) of South 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 likely benign based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BS1). However, 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.Trp24X variant in GJB2 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 patients with hearing loss in trans with at least 4 pathogenic or suspected-pathogenic variants (PM3_VS; PMID:15070423, 24123366, 18941476, 9139825). A knock-in mouse model demonstrates that the p.Trp24X variant leads to the phenotype (PS3; PMID:18941476). 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, BS1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA172240/MONDO:0019497/005

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00029 (4 hom.)
• Consequence: GJB2 NM_004004.6 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:43 B:2
• Conservation: PhyloP100: 7.85

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 10 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.71G>A	p.Trp24Ter	stop_gained	2/2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3	c.71G>A	p.Trp24Ter	stop_gained	2/2		XP_011533351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5	c.71G>A	p.Trp24Ter	stop_gained	2/2	1	NM_004004.6	ENSP00000372299	P1
GJB2	ENST00000382844.2	c.71G>A	p.Trp24Ter	stop_gained	1/1			ENSP00000372295	P1

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152178 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000584 AC: 146 AN: 250040 Hom.: 1 AF XY: 0.000732 AC XY: 99 AN XY: 135286

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00438

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000623

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000294 AC: 430 AN: 1461884 Hom.: 4 Cov.: 32 AF XY: 0.000397 AC XY: 289 AN XY: 727240

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00419

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000261

Gnomad4 OTH exome AF: 0.000613

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152296 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74478

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00353

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000442 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.000576 AC: 70

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:43 Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:18

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Jun 23, 2014	The variant (c. 71G>A, p. W24*) has been previously associated with autosomal recessive hearing loss (Kelsell et al. 1997, PMID: 9139825; Maheshwari et al. 2003, PMID: 12833397; Minarik et al. 2003, PMID: 15113126; Roux et al. 2004, PMID: 15070423; Toth et al. 2004, PMID: 15146474; Alvarez et al. 2005, PMID: 16088916; Bouwer et al. 2007, PMID: 18294064). This variant has been described as the most common GJB2 variant in individuals of Indian descent (2.4% carrier frequency) and Roma descent (4-5% carrier frequency) (Bouwer et al. 2007, PMID: 18294064). This variant is a nonsense variant predicted to create a premature stop codon. Functional analysis suggests that this variant affects the gap junction activity (Mani et al. 2009, PMID: 18941476). Taken together this variant is considered a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Breda Genetics srl	Jun 29, 2021	The variant c.71G>A (p.Trp24*) in the GJB2 gene is reported as a pathogenic for GJB2-related autosomal recessive deafness in ClinVar (Variation ID: 17002). This mutation has been described in multiple papers and is considered common in the Pakistani and Indian population (Richard et al., 2019, PMID: 30303587; Shaik et al., 2017, PMID: 29086887; Santos et al., 2005, PMID: 15617550). It creates a premature stop codon at amino acid position Trp24, which is likely to result in a truncated protein or protein loss due to nonsense-mediated messenger decay (NMD). The variant is reported with an estimated allelic frequency of 0.0006 in gnomAD exomes and 0.0000319 in gnomAD genomes, with one homozygous individual reported. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 12, 2019	NM_004004.5(GJB2):c.71G>A(W24*) is classified as pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. Sources cited for classification include the following: PMID 15070423, 19371219, 15967879, 18941476 and 22695344. Classification of NM_004004.5(GJB2):c.71G>A(W24*) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	research	UAEU Genomics Laboratory, United Arab Emirates University	May 01, 2022	The stop gained NM_004004.6(GJB2):c.71G>A (p.Trp24Ter) variant is an established pathogenic variant reviewed by Clingen hearing Loss expert panel (PMID: 30311386). This variant is one of the common pathogenic variants reported in literature ((PubMed: 9139825, PubMed: 15070423, PubMed: 16088916, PubMed: 31827275, PMID: 30303587), associated with autosomal recessive hearing loss especially in Indian population (PMID: 12833397, PMID: 33614373), with consistent clinical data supporting for pathogenicity. This variant is observed in 134/30616 (0.4377%) alleles from individuals of gnomAD South Asian background in the gnomAD database, which is higher than expected for the disorder, but the evidence for the pathogenicity of this variant for nonsyndromic hearing loss has been determined to outweigh the high allele frequency for classification. The p.Trp24Ter variant in GJB2 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 . This variant has been detected in patients with hearing loss in trans with pathogenic or suspected-pathogenic variants (PMID: 15070423, 24123366, 18941476, 9139825). Functional studies using a knock-in mouse model demonstrated that the p.Trp24Ter variant leads to the phenotype (PMID:18941476). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The substitution creates a nonsense variant within 50 bp downstream of the penultimate exon or last exon. While it is expected to escape nonsense-mediated decay, the truncated region is considered critical. Functional assays showed that the variant had strong level of impact on gene/protein function (PMID: 18941476).This variant has been reported as pathogenic multiple times (ClinVar ID: VCV000017002,PMID:9139825, 3billion database) and observed to be in trans with another pathogenic variant in this gene (PMID: 15070423, 18941476, 24123366, 9139825). It has been reported with an extremely low frequency in the gnomAD v2.1.1 (https://gnomad.broadinstitute.org/) dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	May 20, 2018	PS3, PM1, PM4, PP2, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The GJB2 c.71G>A (p.Trp24Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. Across a selection of the available literature, the p.Trp24Ter variant has been identified in at least 46 patients with a recessive form of nonsyndromic hearing loss including in 28 in a homozygous state, 12 in a compound heterozygous state, and 6 in a heterozygous state (Kelsell et al. 1997; Maheshwari et al. 2003; RamShankar et al. 2003; Alvarez et al. 2005; Salman et al. 2015). The variant has been shown to segregate with disease in an autosomal recessive pattern in affected families (Maheshwari et al. 2003). The p.Trp24Ter variant was reported in five of 285 controls in a heterozygous state, which is consistent with carrier frequency, and is reported at a frequency of 0.00399 in the South Asian population of the Exome Aggregation Consortium. RamShankar et al. (2003) found that the p.Trp24Ter variant was the most common variant among 215 Indian probands and suggested a founder effect was responsible for the estimated carrier frequency of 0.024 in the Indian population. The variant has not been reported in association with Vohwinkel syndrome, ichthyosis hystrix-like with deafness, keratitis-ichthyosis-deafness syndrome or the dominant form of nonsyndromic hearing loss, all conditions known to be caused by variants in the GJB2 gene. Based on the disease prevalence and frequency of the variant, the p.Trp24Ter variant can be ruled out of causing disease in these conditions despite the potential impact of stop-gained variants. However, based on the collective evidence, the p.Trp24Ter variant is classified as pathogenic for the recessive form of nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 28, 2016	Variant summary: The GJB2 c.71G>A (p.Trp24X) 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. Functional analysis showed that this results into truncated protein; the mutant protein does not undergo nonsense mediated decay (Mani_2009). Thus it causes loss of connexin and gap junction channel protein cysteine-rich domains. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.p.Trp44X, p.Gln124X, etc.). This variant was found in 70/121380 control chromosomes at a frequency of 0.0005767, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). In literature, this variant is reported as one of the common pathogenic variants, found especially in India, with consistent clinical (cosegregation and genotypic) data supporting for pathogenicity. Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	A Homozygote Nonsense variant c.71G>A in Exon 2 of the GJB2 gene that results in the amino acid substitution p.Trp24* was identified. The observed variant has a minor allele frequency of 0.00058 in gnomAD exomes and 0.00003 in genomes. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic [Variation ID: 17002]. The observed variation has been previously reported in patients affected with Deafness (Kecskeméti, Nóra et al., 2018). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	research	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	May 15, 2018	- -
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	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 19, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. Multiple truncating variants have previously been reported pathogenic (ClinVar). (N) 0108 - This gene is known to be associated with both recessive and dominant disease (OMIM). (N) 0204 - Variant is predicted to result in a truncated protein with more than 1/3 of the protein affected (exon 2 of 2). (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (145 heterozygotes, 1 homozygote). (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Multiple truncating variants have been previously reported pathogenic (ClinVar) (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has previously been reported in multiple independent cases (ClinVar). (P) 1002 - Moderate functional evidence supporting abnormal protein function. This variant has been shown to result in stop codon readthrough, affecting cellular localisation of the protein (PMID 18941476). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
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	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Dec 08, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Integrating Genomics into Medicine, Frazer Institute, University Of Queensland	Jun 02, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Suma Genomics, Suma Genomics	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2005	- -

not provided Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 04, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 27, 2020	Nonsense variant predicted to result in protein truncation, as the last 203 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014) Classified as pathogenic by the ClinGen Hearing Loss Variant Curation Expert Panel (SCV000840546.3; Oza et al., 2018) This variant is associated with the following publications: (PMID: 31160754, 32847582, 31980526, 31827275, 33111345, 26689913, 18294064, 18941476, 29907799, 30394532, 30168495, 29086887, 29542069, 30094485, 15113126, 14985372, 11968091, 12746422, 16380907, 25636251, 26850479, 26778469, 26059209, 25999548, 9139825, 24840842, 24123366, 22975760, 15070423, 16088916, 12833397) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 19, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 23, 2019	The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity. -
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.Trp24*) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 203 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs104894396, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with autosomal recessive deafness in several families and to be a common cause of the disease in many populations (PMID: 12833397, 15146474, 16088916, 24840842, 26059209). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17002). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on GJB2 function (PMID: 18941476). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 01, 2021	The GJB2 c.71G>A; p.Trp24Ter variant (rs104894396) is a common pathogenic variant reported in association with autosomal recessive hearing loss. In a large multi-center North American cohort it accounted for 1.41% of pathogenic variants identified in GJB2 (33 out of 2,341 variants) (Putcha 2007). This variant is also reported in ClinVar (Variation ID: 17002). This variant induces an early termination codon and 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: Putcha et al. A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort. Genet Med. 2007 Jul;9(7):413-26. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	GJB2: PM3:Very Strong, PVS1:Strong, PM2:Supporting, PS3:Supporting -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -

Hearing impairment Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Pathogenic, no assertion criteria provided	research	Center for Statistical Genetics, Columbia University	Nov 22, 2018	- -
Likely pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	Apr 12, 2021	PVS1_Strong, PS3_Moderate, PM2_Moderate, PP1_Supporting -

Autosomal dominant nonsyndromic hearing loss 3A Pathogenic:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PM3,PM4,PP3,PS1,PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 18, 2015	- -

Hearing loss Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

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

Oct 27, 2014

- -

Nonsyndromic genetic hearing loss Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Sep 17, 2018

The filtering allele frequency of the p.Trp24X variant in the GJB2 gene is 0.38% (137/ 30782) of South 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 likely benign based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BS1). However, 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.Trp24X variant in GJB2 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 patients with hearing loss in trans with at least 4 pathogenic or suspected-pathogenic variants (PM3_VS; PMID: 15070423, 24123366, 18941476, 9139825). A knock-in mouse model demonstrates that the p.Trp24X variant leads to the phenotype (PS3; PMID:18941476). 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, BS1. -

Mutilating keratoderma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

GJB2-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 27, 2024

The GJB2 c.71G>A variant is predicted to result in premature protein termination (p.Trp24*). This variant has been reported as causative for autosomal recessive hearing loss (Alvarez et al. 2005. PubMed ID: 16088916; Santos et al. 2005. PubMed ID: 15617550; Mani et al. 2009. PubMed ID: 18941476; Pavithra et al. 2014. PubMed ID: 24840842). This is the most common GJB2 variant in individuals of Indian and Roma descent (Bouwer et al. 2007. PubMed ID: 18294064). This variant is reported in 0.44% of alleles in individuals of South Asian descent in gnomAD. Nonsense variants in GJB2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

Palmoplantar keratoderma-deafness syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

- -

Hearing loss, autosomal recessive Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

-

- -

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

Dec 07, 2021

- -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 25, 2008

The Trp24X variant in GJB2 is a known pathogenic variant and has been reported i n many individuals affected with hearing loss (Kelsell 1997, Roux 2004, Mani 200 9). ACMG/AMP Criteria applied: PVS1, PM3_VeryStrong. -

Ichthyosis, hystrix-like, with hearing loss Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	45
DANN	Uncertain	0.99
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.97	D
MutationTaster	Benign	1.0	A;A
Vest4		0.87
GERP RS		5.2

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: rs104894396; hg19: chr13-20763650;