13-20189546-AC-A
Variant summary
Our verdict is Pathogenic. Variant got 6 ACMG points: 14P and 8B. PM3PS4PVS1BA1
This summary comes from the ClinGen Evidence Repository: The c.35delG variant in GJB2 is predicted to cause a premature stop codon in biologically-relevant-exon 2/2 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:26445815). This variant was found to have a statistically higher prevalence in affected individuals over controls (PS4; PMID:26969326, 25999548). The filtering allele frequency of the c.35delG variant in the GJB2 gene is 0.9% for European (Non-Finnish) chromosomes in the Genome Aggregation Database (1207/124552 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). The ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for hearing loss outweighs the high allele frequency of the variant in population databases. Therefore, the BA1 code will not contribute to the overall classification. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PVS1, PM3_VS, PS4, BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA127023/MONDO:0019497/005
Frequency
Consequence
NM_004004.6 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| GJB2 | ENST00000382848.5 | c.35delG | p.Gly12ValfsTer2 | frameshift_variant | Exon 2 of 2 | 1 | NM_004004.6 | ENSP00000372299.4 | ||
| GJB2 | ENST00000382844.2 | c.35delG | p.Gly12ValfsTer2 | frameshift_variant | Exon 1 of 1 | 6 | ENSP00000372295.1 |
Frequencies
GnomAD3 genomes 0.00627 AC: 952AN: 151764Hom.: 4 Cov.: 32
GnomAD3 exomes AF: 0.00597 AC: 1488AN: 249362Hom.: 7 AF XY: 0.00599 AC XY: 808AN XY: 134954
GnomAD4 exome AF: 0.00713 AC: 10423AN: 1461600Hom.: 34 Cov.: 32 AF XY: 0.00701 AC XY: 5100AN XY: 727098
GnomAD4 genome 0.00627 AC: 952AN: 151882Hom.: 4 Cov.: 32 AF XY: 0.00601 AC XY: 446AN XY: 74244
ClinVar
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:34Other:1
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are mechanisms of disease in this gene. Whilst loss of function has been demonstrated for protein truncating variants, the gene mechanism for missense variants is not well established, although loss of function and dominant negative have been suggested (PMID: 19384972; PMID: 28428247). (I) 0108 - This gene is known to be 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 - Variants in this gene are known to have reduced penetrance, reported to be associated with the p.M34T and p.V37I missense variants (PMID: 31160754). (I) 0204 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with at least 1/3 of the protein sequence affected. (SP) 0251 - Variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 1717 heterozygotes, 10 homozygotes). (SP) 0701 - Other protein truncating variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many downstream protein truncating variants have been reported as pathogenic (ClinVar; Decipher). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reviewed by expert panel to be pathogenic and is known to have variable expressivity, ranging from mild to profound deafness (ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
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The variant GJB2: c.35delG, p.Gly12Valfs*2, which is located in the coding exon 2 of the GJB2 gene, results from a deletion of a base at nucleotide position c.35. The variant causes a frameshift that results in the replace of a glycine by a valine at protein position 12, followed by a premature translation stop codon after two amino acids. Degradation of the truncated gene product due to non-sense mediated decay is not predicted. However, a large part of the protein is lost, including the functionally relevant connexin domain.The variant was described in an Italian study as the most common GJB2 variant associated with autosomal recessive non-syndromic hearing loss (PMID: 12176036). Multiple studies showed an increased prevalence on individuals affected with hearing loss (PMID: 26969326, 25999548). A cell culture-based functional study showed that the altered gene product is no longer detectable and leads to a loss of function of GJB2 (PMID: 12176036). The variant is not considered rare in the overall population (allele frequency= 0.007050 in gnomAD, v4.1.0). The variant has been consistently classified as Pathogenic in more than 80 entries in ClinVar (ClinvarID: 17004). The ClinGen Expert panel for hearing disorders classified this variant as Pathogenic despite the comparatively high allele frequency. In summary, the variant is classified as Pathogenic. -
The GJB2 c.35delG (p.G12fs) frameshift variant is reported as the most common pathogenic variant associated with autosomal recessive nonsyndromic hearing loss (PMID: 9285800; 9328482; 9819448; 12176036; 20301449). -
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ACMG classification criteria: PVS1 very strong, PS4 strong, PM3 very strong -
NM_004004.5(GJB2):c.35delG(aka p.G12Vfs*2) is classified as pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. Sources cited for classification include the following: PMID 12176036, 24158611, 19371219, 15967879, 16380907. Classification of NM_004004.5(GJB2):c.35delG(aka p.G12Vfs*2) 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. -
Variant summary: The GJB2 c.35delG (p.Gly12Valfs) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g., c.71G>A [p.Trp24X], c.131G>A [p.Trp44X], and c.167delT [p.Leu56fs). This variant was found in 733/122042 control chromosomes (3 homozygotes) including ExAC at a frequency of 0.0060061, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). This variant is known to be the most common pathogenic GJB2 variant worldwide that causes autosomal recessive nonsyndromic hearing loss. Immunochemistry studies showed that the variant does not produce detectable protein and prevents normal intercellular molecular transfer (D'Andrea_BBRC_2002). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
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The GJB2 c.35delG (p.Gly12ValfsTer2) variant, which results in a frameshift and is predicted to result in premature termination of the protein, is one of the most common variants associated with the recessive form of nonsyndromic hearing loss, DFNB1, with more than half of all persons of northern European ancestry with two identifiable GJB2 mutations being homozygous for this variant (Scott et al. 1998). Across a small selection of the available literature, the p.Gly12ValfsTer2 variant has been identified in a homozygous state in 89 individuals with hearing loss, in a compound heterozygous state in 23 affected individuals, and in a heterozygous state in 11 affected individuals in whom a second variant was not identified (Zelante et al. 1997; Estivill et al. 1998; Murgia et al. 1999; Snoeckx et al. 2005). The p.Gly12ValfsTer2 variant was identified in a total of ten of 800 control chromosomes and is reported at a frequency of 0.0152 in the Utah residents with Northern and Western European ancestry population of the 1000 Genomes Project which is consistent with the carrier frequency for p.Gly12ValfsTer2 (Snoeckx et al. 2005). Based on the potential impact of frameshift variants and the evidence from the literature the p.Gly12ValfsTer2 variant is classified as pathogenic for recessive 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 p.Gly12Valfs*2 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.Val37Ile, p.Met34Thr), consistent with autosomal recessive inheritance (Sloan-Heggen 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.Gly12Valfs*2 variant has also been identified in 1,217/127,068 European chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, its frequency is consistent with a recessive carrier frequency for hearing loss. This variant results in a 1 bp deletion, which causes a shift in the protein reading frame, leading to a premature termination codon 2 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.Gly12Valfs*2 variant as pathogenic for autosomal recessive nonsyndromic hearing loss based on the information above. [ACMG evidence codes used: PVS1; PM3_verystrong] -
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The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense variant Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000011035 /PMID: 12930312, 9683615).The variant has been previously reported as de novo in a similarly affected individual (PMID: 27054699).The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 22428923, 25333067, 27305980).The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 18231121, 18821982, 20486090, 26273176). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
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The c.35delG (p.Gly12Valfs*2) frameshift variant introduces a premature stop codon, leading to the truncation of the Connexin 26 protein. The c.35delG variant represents the most common pathogenic variant in Caucasian patients with genetic sensorineural deafness (Carrasquillo et al. 1997; Denoyelle et al. 1997; Zelante et al. 1997; Green et al. 1999; Gasparini et al. 2000; Kenneson et al. 2002; Bouwer et al. 2007). Therefore, this collective evidence supports the classification of the c.35delG (p.Gly12Valfs*2) as a Pathogenic variant for Nonsyndromic hearing loss. -
Criteria applied: PVS1,PM3_VSTR -
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We found this variant in a patient with hearing impairment in a homozygous state. -
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The GJB2 variant (c.35delG, p.Gly12Valfs*2) identified in this patient is a frameshift variant, reported to be the most common pathogenic variant in individuals with European ancestry (Carrasquillo et al. 1997, PMID: 9328482; Denoyelle et al. 1997, PMID: 9336442; Zelante et al. 1997, PMID: 9285800; Green et al. 1999, PMID: 10376574; Gasparini et al. 2000, PMID: 10713883; Kenneson et al. 2002, PMID: 12172392; Bouwer et al. 2007, PMID: 18294064). -
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The frameshift deletion NM_004004.6(GJB2):c.35delG (p.Gly12Valfs*2) is reported to be the most common pathogenic variant in GJB2 associated with Autosomal Recessive Deafness 1A (DFNB1A) across different ethnic groups and reported in homozygous and compound heterozygous states (PubMed: 9285800, 10422812, 10713883, 11313751, 11483639, 26445815). This variant has been curated as Pathogenic by ClinGen hearing loss Expert panel members (PMID: 30311386). Though this variant is observed in 1027/111668 (0.92%) alleles in the gnomAD database, studies suggests that the carrier frequency of this variant can reach up to 2%-4% (PMID: 16380907). The p.Gly12Valfs*2 variant is predicted to cause loss of normal protein function through protein truncation caused a frameshift mutation. Published in vitro functional studies demonstrated that the variation leads to the absence of functional protein and activity (PubMed: 12176036). For these reasons, this variant has been classified as Pathogenic. -
PVS1, PM3_VS, PS4 -
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PVS1, PS3, PM1, PP5 -
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This sequence variant is a single nucleotide deletion (delG) in exon 2 of 2 of GJB2 and results in a premature termition sigl 2 codons downstream of the frameshift introduced at the Gly12 residue. The c.35del allele may be referred to as 35delG in the literature and online databases. This variant generates a non-functiol allele through either the expression of a truncated protein or a loss of Connexin 26 expression due to nonsense mediated decay (PMID: 12176036). This variant is present in 0.6% of control population datasets (gnomAD database, 1737 of 280696, 0.62%) and is one of the most frequent alleles associated with Connexin 26-related non-syndromic hearing loss (PMID: 12176036, 16650073, 12172392). This variant has been observed in both the homozygous and compound heterozygous state in individuals affected with hearing loss (PMID: 12176036, 16650073, 12172392, 19371219, 26969326) and has been assessed as pathogenic by an expert panel since 2019 (ClinGen Hearing Loss Variant Curation Expert Panel, accession: SCV000840537.3). Based on this evidence, we consider this a pathogenic variant. ACMG Criteria: PM3, PS4, PVS1 -
This variant was identified in compound heterozygosity with a second variant in GJB2 in 2 different male patients with congenital bilateral moderate hearing loss. -
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not provided Pathogenic:18
GJB2: PM3:Very Strong, PVS1:Strong, PM2:Supporting, PS3:Supporting -
PM3_very_strong, PS4, PVS1 -
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Case control studies suggest this variant is associated with hearing loss; allele frequency of the variant is significantly higher in individuals with hearing loss compared to individuals in the general population (Tsukada et al., 2015; Sloan-Heggen et al., 2016); Frameshift variant predicted to result in protein truncation, as the last 214 amino acids are lost (Stenson et al., 2014); In vitro studies demonstrate that the c.35delG variant results in loss of connexin 26 function (D'Andrea et al., 2002); Classified as pathogenic by the ClinGen Hearing Loss Variant Curation Expert Panel (SCV000840537.3; Oza et al., 2018); This variant is associated with the following publications: (PMID: 20815033, 22975760, 26896187, 29234782, 9819448, 18985073, 25262649, 12833397, 16088916, 21465647, 15070423, 20073550, 19925344, 20739944, 23489192, 27316387, 17666888, 16222667, 27843504, 12189487, 14738110, 25266519, 9285800, 27153395, 26990548, 19274344, 27177047, 25533962, 29501291, 29293505, 29431110, 29016196, 28281779, 17431919, 12169891, 12172392, 30609409, 30730013, 30094485, 29372807, 29542069, 29086887, 30168495, 30390570, 30431684, 31163360, 29907799, 30055715, 31028937, 31370293, 31162818, 30344259, 31564438, 31130284, 31541171, 32279305, 31827275, 31980526, 31160754, 30275481, 10782932, 32747562, 33443819, 14759569, 33096615, 29871260, 33297549, 12068628, 33466560, 33105617, 32067424, 32853555, 32860223, 11355484, 32842620, 31078570, 10713883, 12176036, 26969326, 25999548) -
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The GJB2 c.35del; p.Gly12ValfsTer2 variant (rs80338939, ClinVar Variation ID 17004) is the most common pathogenic GJB2 variant found among individuals with European ancestry (Estivill 1998, Gasparini 2000, Putcha 2007). It has been reported in both homozygous and compound heterozygous state in individuals with autosomal recessive nonsyndromic hearing loss with severity ranging from mild to profound (Alkhidir 2024, Estivill 1998, Yan 2024). This variant is found in the general population with an overall allele frequency of 0.62% (1737/280696 alleles, including 10 homozygotes) in the Genome Aggregation Database (v2.1.1). This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. In vitro expression studies with mutant protein demonstrate a complete loss of connexin 26 in transfected cells (D'Andrea 2002). Based on available information, this variant is considered to be pathogenic. References: Alkhidir S et al. The genetic basis and the diagnostic yield of genetic testing related to nonsyndromic hearing loss in Qatar. Sci Rep. 2024 Feb 20. PMID: 38378725. D'Andrea P et al. Hearing loss: frequency and functional studies of the most common connexin26 alleles. Biochem Biophys Res Commun. 2002 Aug 23. PMID: 12176036. Estivill X et al. Connexin-26 mutations in sporadic and inherited sensorineural deafness. Lancet. 1998 Feb 7. PMID: 9482292. Gasparini P et al. High carrier frequency of the 35delG deafness mutation in European populations. Genetic Analysis Consortium of GJB2 35delG. Eur J Hum Genet. 2000 Jan. PMID: 10713883. Putcha GV 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. PMID: 17666888. Yan D et al. Etiologic Diagnosis of Genetic Hearing Loss in an Ethnically Diverse Deafness Cohort. Audiol Neurootol. 2024 Aug 23. PMID: 39182490. -
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The c.35delG deletion is the most common pathogenic variant associated with hearing loss. Www.ncbi.nlm.nih.gov/books/NBK1272/1 -
This sequence change creates a premature translational stop signal (p.Gly12Valfs*2) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 215 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs80338939, gnomAD 1.0%), 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 (PMID: 9285800, 9328482, 12239718). It is commonly reported in individuals of European ancestry (PMID: 10751669, 12172392, 12176036, 12239718, 19925344). ClinVar contains an entry for this variant (Variation ID: 17004). 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 have shown that this premature translational stop signal affects GJB2 function (PMID: 12176036). For these reasons, this variant has been classified as Pathogenic. -
This variant is expected to result in the loss of a functional protein. This variant is one of the most common variants associated with the recessive form of nonsyndromic hearing loss, DFNB1 (PMID: 20301449), and so therefore the frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant is also referred to as 35delG, and sometimes 30delG, in published literature. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. In vitro studies demonstrate this variant results in loss of connexin 26 function (PMID: 12176036). -
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Hearing impairment Pathogenic:6
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PVS1_Strong, PS3_Strong -
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Hearing loss, autosomal recessive Pathogenic:4Other:1
This sequence change in GJB2 is a frameshift variant predicted to create a premature stop codon, p.(Gly12Valfs*2), in biologically relevant exon 2/2 , expected to escape nonsense-mediated decay, however it is a truncation of a functionally important region (removes amino acids 13-226) in a gene where loss-of-function is an established disease mechanism (PMID: 20301449). The highest population minor allele frequency in the population database gnomAD v4.1 is 0.8% (9,758/1,179,762 alleles, 30 homozygotes) in the European (non-Finnish) population, which is higher than expected for a recessive disease. However, this variant is the most common cause GJB2-related deafness in the European population. This variant has been detected as homozygous and compound heterozygous in multiple individuals with sensorineural hearing loss, with at least one pathogenic variant confirmed on the second allele (PMID: 35396755, 34440441, 16950989, 16380907, 33524517). The variant segregates with deafness in multiple families (PMID: 34440441, 33524517). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.7.0, this variant is classified as PATHOGENIC. Following criteria are met: PVS1_Strong, PM3_VeryStrong, PP1_Strong, BA1 -
Variant identified in multiple participants. Variant interpreted as Pathogenic and reported on 10-31-2014 by Lab or GTR ID 50489, reported on 03-17-2020 by Lab or GTR ID 21766, and reported on 11/16/2015 by GTR ID 165021. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
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GJB2-related disorder Pathogenic:4
PVS1, PM3_VS, PS4, BA1 -
This variant is also referred to as 35delG or 30delG in the literature (PMID: 12176036). This frameshift variant is found in exon 2 of 2 of the GJB2 gene, therefore the resulting mRNA is predicted to escape nonsense-mediated decay. However, frameshift variants located downstream of this variant have been reported as disease-causing variants in the literature (PMID: 20301449). Loss-of-function variation in GJB2 is an established mechanism of disease (PMID: 20301449). This is a known Pathogenic variant and it has been previously reported as a compound heterozygous or homozygous change in individuals with nonsyndromic hearing loss (PMID: 9285800, 9819448, 12176036, 14738110, 16380907, 20301449). This variant was found to have a statistically higher prevalence in affected individuals over controls (PMID: 26969326, 25999548). In vitro functional studies have shown that the c.35del (p.Gly12ValfsTer2) variant impairs proper assembly and function of the gap junction channels (PMID: 12176036). The c.35del (p.Gly12ValfsTer2) variant is present in the gnomAD v4 population database at a frequency of 0.7% (11299/1613482) in the heterozygous state and reported in 38 individuals in the homozygous state. Based on the available evidence, c.35del (p.Gly12ValfsTer2) is classified as Pathogenic. -
PVS1, PS4, PM3_Very Strong -
The GJB2 c.35delG variant is predicted to result in a frameshift and premature protein termination (p.Gly12Valfs*2). This variant has been reported to be one of the most common causative variants for autosomal recessive nonsyndromic hearing loss and deafness (Wilcox et al. 2000. PubMed ID: 10830906; D'Andrea et al. 2002. PubMed ID: 12176036; Chan et al. 2010. PubMed ID: 20154630; Dzhemileva et al. 2010. PubMed ID: 20739944). This variant is interpreted as pathogenic. -
Autosomal dominant keratitis-ichthyosis-hearing loss syndrome;C0265964:Mutilating keratoderma;C0266004:Knuckle pads, deafness AND leukonychia syndrome;C1835672:Palmoplantar keratoderma-deafness syndrome;C1865234:Ichthyosis, hystrix-like, with hearing loss;C2673759:Autosomal recessive nonsyndromic hearing loss 1A;C2675750:Autosomal dominant nonsyndromic hearing loss 3A Pathogenic:3
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GJB2 NM_004004.5 exon 2 p.Gly12Valfs*2 (c.35delG): This variant is reported to be one of the most common pathogenic GJB2 variants; it has been reported in the literature in the homozygous or compound heterozygous state in numerous individuals with autosomal recessive nonsyndromic hearing loss (Carrasquillo 1997 PMID: 9328482; Denoyelle 1997 PMID: 9336442; Zelante 1997, PMID: 9285800; Green 1999 PMID: 10376574; Gasparini 2000 PMID: 10713883; Kenneson 2002 PMID: 12172392; Bouwer 2007 PMID: 18294064). This variant is present in 0.9% (1217/127068) of European alleles in the Genome Aggregation Database, including 4 homozygotes (http://gnomad.broadinstitute.org/variant/13-20763685-AC-A). Please note, disease causing variants may be present in control databases, reflective of the general population, carrier frequency, and/or variable expressivity. This variant is present in ClinVar, with multiple reporting labs classifying this variant as pathogenic (Variation ID:17004). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. In vitro functional studies predict that this variant will impact the protein and result in loss of connexin 26 function (D'Andrea 2002 PMID: 12176036). However, these studies may not accurately represent in vivo biological function. This variant is a deletion of one nucleotide and creates a premature stop codon 2 amino acids downstream from this location, which results in an absent or abnormal protein. Loss of function variants are commonly reported in association with disease for this gene (Choi 2011 PMID:21298213). In summary, this variant is classified as pathogenic based on the data above. -
Autosomal dominant nonsyndromic hearing loss 3A Pathogenic:3
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This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM1. This variant was detected in homozygous state. -
Nonsyndromic genetic hearing loss Pathogenic:2
The c.35delG variant in GJB2 is predicted to cause a premature stop codon in biologically-relevant-exon 2/2 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: 26445815). This variant was found to have a statistically higher prevalence in affected individuals over controls (PS4; PMID: 26969326, 25999548). The filtering allele frequency of the c.35delG variant in the GJB2 gene is 0.9% for European (Non-Finnish) chromosomes in the Genome Aggregation Database (1207/124552 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). The ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for hearing loss outweighs the high allele frequency of the variant in population databases. Therefore, the BA1 code will not contribute to the overall classification. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PVS1, PM3_VS, PS4, BA1. -
Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: PVS1, PM3_VS, PS4 -
Knuckle pads, deafness AND leukonychia syndrome Pathogenic:2
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Bilateral sensorineural hearing impairment;C1384666:Hearing impairment Pathogenic:1
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Hearing loss Pathogenic:1
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Inborn genetic diseases Pathogenic:1
The c.35delG (p.G12Vfs*2) alteration, located in exon 2 (coding exon 1) of the GJB2 gene, consists of a deletion of one nucleotide at position 35, causing a translational frameshift with a predicted alternate stop codon after 2 amino acids. The GJB2 gene has a single coding exon, so while the alteration is truncating, the mRNA is not predicted to undergo nonsense mediated decay (NMD) and a truncated mutant protein could still be expressed. Premature termination codons located either in the last exon or within 50-55 nucleotides upstream of the 3’-most exon-exon junction usually fail to elicit NMD (Maquat, 2004). The exact functional impact of these altered amino acids is unknown at this time; however, this alteration and additional truncating alterations downstream of this alteration have been reported in the literature as disease-causing (Roux, 2004). Based on data from gnomAD, the - allele has an overall frequency of 0.619% (1737/280696) total alleles studied. The highest observed frequency was 0.958% (1217/127068) of European (non-Finnish) alleles. The c.35delG variant is the most common GJB2 pathogenic variant among Caucasians individuals, and has been reported in patients with mild to profound hearing loss of multiple ethnicities (Denoyelle, 1997; Gasparini, 2000; Gualandi, 2002; Roux, 2004; Hilgert, 2009; Mahdieh, 2016; Zytsar, 2018). Additionally, this variant was observed in trans with p.N176D in multiple families with syndromic hearing loss with ectodermal involvement (Youssefian, 2018; Youssefian, 2022). Functional studies show an absence of protein expression and reduced intercellular diffusion of dye in vitro (D'Andrea, 2002). Based on the available evidence, this alteration is classified as pathogenic. -
Deafness, digenic, GJB2/GJB6 Pathogenic:1
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Bilateral sensorineural hearing impairment Pathogenic:1
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Autosomal recessive nonsyndromic hearing loss 1A;C2675235:Autosomal recessive nonsyndromic hearing loss 1B Pathogenic:1
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Deafness Pathogenic:1
The c.35delG variant is a deletion of one guanine in a sequence of six guanines in the GJB2 coding sequence leading to premature chain termination at the twelfth amino acid of the Cx26 protein p.(Gly12Valfs*2) - PVS_strong. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 16773579; 12176036) - PS3_supporting. This variant is the most common in Caucasian populations and is described as pathogenic in the specialized literature, being one of the most common variant associated with non-syndromic deafness phenotype (ClinVar ID: 17004, ClinGen: CA127023, OMIM: 121011.0005, PMID: 20301449, 16773579, 34440441) – PS4. The c.35delG was detected in trans with a pathogenic variant (PMID: 21220926, 26096904, 24039984, 14694360, 34440441, 16849369) – PM3_very strong; and co-segregated with deafnes in multiple affected family members (PMID: 16773579, 24039984, 14694360) – PP1. This variant is observed in the general population (rs80338939 - gnomAD 0,006 frequency; ABraOM 0,0098 frequency - http://abraom.ib.usp.br/). In summary, the currently available evidence indicates that the variant is pathogenic. -
Autosomal recessive nonsyndromic hearing loss 104 Pathogenic:1
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Bilateral conductive hearing impairment;C1384666:Hearing impairment Pathogenic:1
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Rare genetic deafness Pathogenic:1
The c.35delG variant in GJB2 is known to be pathogenic with many supporting publications. ACMG/AMP Criteria applied: PVS1, PM3_VeryStrong. -
Ear malformation Pathogenic:1
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Severe sensorineural hearing impairment Pathogenic:1
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Hereditary palmoplantar keratoderma Pathogenic:1
PVS1_PM3_VertStrong -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at