rs104894396
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 14P and 4B. PM3PS3BS1PVS1
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
Consequence
NM_004004.6 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.000138 AC: 21AN: 152178Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000584 AC: 146AN: 250040Hom.: 1 AF XY: 0.000732 AC XY: 99AN XY: 135286
GnomAD4 exome AF: 0.000294 AC: 430AN: 1461884Hom.: 4 Cov.: 32 AF XY: 0.000397 AC XY: 289AN XY: 727240
GnomAD4 genome 0.000138 AC: 21AN: 152296Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13AN XY: 74478
ClinVar
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:19
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. -
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. -
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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. -
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. -
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. -
ACMG codes:PVS1, PM2, PP5 -
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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 -
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PS3, PM1, PM4, PP2, PP3 -
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The observed stop gained variant c.71G>A p.Trp24Ter in GJB2 gene has been reported in homozygous, compound heterozygous state in multiple individuals with deafness Kecskeméti et al., 2018, Kausar N, et al., 2021. Experimental studies have shown that this variant leads to formation of defective protein Mani et. al., 2009. The p.Trp24Ter variant is reported with an allele frequency of 0.05% in the gnomAD exomes. This variant has been reported to the ClinVar database as Likely Benign/ Likely Pathogenic/ Pathogenic multiple submissions. The nucleotide change c.71G>A in GJB2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Computational evidence Mutation Taster - Disease causing predicts damaging effect on protein structure and function for this variant. This variant is predicted is expected to disrupt the last 203 amino acids of the GJB2 protein. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -
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. -
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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. -
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. -
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not provided Pathogenic:10
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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 gene product 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. -
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GJB2: PM3:Very Strong, PVS1:Strong, PM2:Supporting, PS3:Supporting -
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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. PMID: 17666888. -
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) -
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. -
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Hearing impairment Pathogenic:4
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PVS1_Strong, PS3_Moderate, PM2_Moderate, PP1_Supporting -
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Autosomal dominant nonsyndromic hearing loss 3A Pathogenic:2Benign:1
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PM3,PM4,PP3,PS1,PP4. -
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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. -
Hearing loss Pathogenic:1
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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
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Nonsyndromic genetic hearing loss Pathogenic:1
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
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GJB2-related disorder Pathogenic:1
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
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Palmoplantar keratoderma-deafness syndrome Pathogenic:1
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Knuckle pads, deafness AND leukonychia syndrome Pathogenic:1
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Hearing loss, autosomal recessive Pathogenic:1
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Rare genetic deafness Pathogenic:1
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. -
Hereditary palmoplantar keratoderma Pathogenic:1
PVS1,PS3,PM3,BS1 -
Ichthyosis, hystrix-like, with hearing loss Benign:1
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at