rs80338943
Variant summary
Our verdict is Pathogenic. Variant got 8 ACMG points: 12P and 4B. PM3PS3_ModerateBS1PVS1
This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the p.Leu79CysfsX3 variant in the GJB2 gene is 0.55% (121/ 18870) of East 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 benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BS1). 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.Leu79CysfsX3 variant in GJB2 is predicted to cause a premature stop codon in the only exon of the gene, leading to 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:10983956, 10633133). A dye transfer assay, a functional study, has shown that the variant impacts protein function (PS3_M; PMID:12352684). 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_M, BS1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA127025/MONDO:0019497/005
Frequency
Consequence
NM_004004.6 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| GJB2 | ENST00000382848.5 | c.235delC | p.Leu79CysfsTer3 | frameshift_variant | Exon 2 of 2 | 1 | NM_004004.6 | ENSP00000372299.4 | ||
| GJB2 | ENST00000382844.2 | c.235delC | p.Leu79CysfsTer3 | frameshift_variant | Exon 1 of 1 | 6 | ENSP00000372295.1 |
Frequencies
GnomAD3 genomes 0.000302 AC: 46AN: 152196Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000469 AC: 118AN: 251392Hom.: 0 AF XY: 0.000434 AC XY: 59AN XY: 135884
GnomAD4 exome AF: 0.000180 AC: 263AN: 1461826Hom.: 0 Cov.: 33 AF XY: 0.000182 AC XY: 132AN XY: 727212
GnomAD4 genome 0.000302 AC: 46AN: 152314Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25AN XY: 74494
ClinVar
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:16Other:1
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NM_004004.5(GJB2):c.235delC(aka L79Cfs*3) is classified as pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. Sources cited for classification include the following: 12505163, 20095872, 20497192, 16380907, and 15937416. Classification of NM_004004.5(GJB2):c.235delC(aka L79Cfs*3) 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.235delC (p.Leu79Cysfs) 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. Mutation taster predicts a damaging outcome for this variant. It was found in 44/121376 control chromosomes at a frequency of 0.0003625, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). The variant was reported in several autosomal recessive non-syndromic hearing loss patients either in homozygosity or in compound heterozygosity with other pathogenic GJB2 variants indicating pathogenicity. Additionally, a functional study demonstrated the variant to result in a truncated form of GJB2 which is not capable to facilitate junctional conductance, further supporting a deleterious impact. Moreover, multiple clinical diagnostic laboratories classified this variant as Pathogenic. Taken together, this variant is classified as pathogenic. -
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Frameshift: predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_S). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 12352684, PS3_M). The variant has been reported multiple times as an established pathogenic/likely pathogenic variant (ClinVar ID: VCV000017014, PMID:10501520, 3billion dataset). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000474, PM2_M). The same variant was previously reported several times in trans with another pathogenic variant in this gene (PMID: 10983956, 10633133, PM3_VS). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
PVS1+PM3_VeryStrong+PS3_Moderate+BS1 -
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Based on the classification scheme VCGS_Germline_v1.3.3, 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 (v2) <0.01 for a recessive condition (134 heterozygotes, 0 homozygotes). (SP) 0701 – Other truncating variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by the ClinGen Hearing Loss Variant Curation Expert Panel and has multiple pathogenic entries in ClinVar. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
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This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
not provided Pathogenic:7
One of the most common variants reported in the GJB2 gene, with a carrier frequency of 1-2% in the Japanese and Chinese populations (Fuse et al., 1999; Dzhemileva et al., 2010; Yao et al., 2012); Frameshift variant predicted to result in protein truncation, as the last 148 amino acids are lost and replaced with 2 incorrect amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Published functional studies demonstrate a damaging effect; cells expressing c.235delC fail to reach their destination in the cell membrane and have reduced gap junction activity (Choung et al., 2002; Zhang et al., 2010); Classified as pathogenic by the ClinGen Hearing Loss Expert Panel (SCV000840502.3; Oza et al., 2018); This variant is associated with the following publications: (PMID: 12505163, 26336802, 25266519, 26119842, 30275481, 20095872, 25262649, 22975760, 12352684, 23469187, 24945352, 22088281, 15479191, 22747691, 20739944, 17666888, 10501520, 19043807, 26061264, 26763877, 27308839, 27045574, 28012523, 16952406, 12111646, 12169891, 30282152, 29447821, 30589569, 29086887, 29771057, 30693673, 31195736, 30816908, 30036422, 30146550, 31370293, 30733538, 31347505, 31162818, 30344259, 31564438, 29625052, 31914302, 26689913, 31541171, 31827275, 31980526, 31160754, 30896630, 32747562, 22875492, 31589614, 29871260, 32973888, 32708339) -
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This variant is expected to result in the loss of a functional protein. This variant is one of the most common variants associated with autosomal recessive form of nonsyndromic hearing loss (PMID: 17505205, 19043807, 15700112), 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 appears to segregate with disease in at least one family. Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiments show this variant impairs gap junction channel activity (PMID: 12352684, 12505163). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. -
The GJB2 c.235del; p.Leu79CysfsTer3 variant (rs80338943) is a well-studied variant associated with autosomal recessive nonsyndromic hearing loss (Choung 2002, Du 2016, Fuse 1999, Han 2008, Zhang 2010). This variant is reported in ClinVar (Variation ID: 17014) and is found in the general population with an overall allele frequency of 0.047% (134/282,792 alleles) in the Genome Aggregation Database. 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. Based on available information, this variant is considered to be pathogenic. References: Choung YH et al. Functional study of GJB2 in hereditary hearing loss. Laryngoscope. 2002 Sep;112(9):1667-71. PMID: 12352684. Du Y et al. Analysis of p.V37I compound heterozygous mutations in the GJB2 gene in Chinese infants and young children. Biosci Trends. 2016 Jul 19;10(3):220-6. PMID: 27350192. Fuse Y et al. Three novel connexin26 gene mutations in autosomal recessive non-syndromic deafness. Neuroreport. 1999 Jun 23;10(9):1853-7. PMID: 10501520. Han SH et al. Carrier frequency of GJB2 (connexin-26) mutations causing inherited deafness in the Korean population. J Hum Genet. 2008;53(11-12):1022-8. PMID: 19043807. Zhang Y et al. Three common GJB2 mutations causing nonsyndromic hearing loss in Chinese populations are retained in the endoplasmic reticulum. Acta Otolaryngol. 2010 Jul;130(7):799-803. PMID: 20095872. -
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This sequence change creates a premature translational stop signal (p.Leu79Cysfs*3) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 148 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs80338943, gnomAD 0.6%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individuals with autosomal recessive non-syndromic hearing loss (PMID: 10501520, 15479191, 17505205, 20739944, 22747691, 25266519, 26061264, 27045574). It is commonly reported in individuals of East Asian ancestry (PMID: 14505035). This variant is also known as c.233delC. ClinVar contains an entry for this variant (Variation ID: 17014). 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: 12352684, 20095872). For these reasons, this variant has been classified as Pathogenic. -
Hearing loss Pathogenic:1
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Deafness, digenic, GJB2/GJB3 Pathogenic:1
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Autosomal recessive nonsyndromic hearing loss 1A;C2675750:Autosomal dominant nonsyndromic hearing loss 3A 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.Leu79CysfsX3 variant in the GJB2 gene is 0.55% (121/ 18870) of East 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 benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BS1). 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.Leu79CysfsX3 variant in GJB2 is predicted to cause a premature stop codon in the only exon of the gene, leading to 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: 10983956, 10633133). A dye transfer assay, a functional study, has shown that the variant impacts protein function (PS3_M; PMID: 12352684). 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_M, BS1. -
Hearing impairment Pathogenic:1
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Autism spectrum disorder Pathogenic:1
Among 16 children with non-syndromic sensorineural hearing loss and carried GJB2 mutations, 44% had additional disabilities, including specific learning disability, apraxia, epileptiform aphasia, attention deficit disorder, global developmental delay, and gross motor delay (PMID: 16154643). In our study, four children diagnosed with Autism Spectrum Disorder are carriers of this rs80338943 mutation. -
Rare genetic deafness Pathogenic:1
The c.235delC variant in GJB2 is a well-studied pathogenic variant (Abe 2000, Pa rk 2000, Choung 2002, Liu 2002, Ohtsuka 2003, Yao 2012). This variant is predict ed to cause a frameshift, which alters the protein's amino acid sequence beginni ng at codon 79 and leads to a premature termination codon 3 amino acids downstre am. This alteration is then predicted to lead to a truncated or absent protein. In summary, this variant meets criteria to be classified as pathogenic for heari ng loss in an autosomal recessive manner. ACMG/AMP Criteria applied: PVS1, PM3_ VeryStrong. -
Autosomal dominant nonsyndromic hearing loss 3A 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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GJB2-related disorder Pathogenic:1
The GJB2 c.235delC variant is predicted to result in a frameshift and premature protein termination (p.Leu79Cysfs*3). This variant has been reported to be causative for autosomal recessive non-syndromic hearing loss (Hwa et al. 2003. PubMed ID: 12792423; Chan et al. 2010. PubMed ID: 20154630; Pang et al. 2014. PubMed ID: 24945352; Xia et al. 2016. PubMed ID: 27045574). This variant is reported in 0.65% of alleles in individuals of East Asian descent in gnomAD. Frameshift variants in GJB2 are expected to be pathogenic. This variant is interpreted as pathogenic by the ClinGen Hearing Loss Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/17014/). We classify this variant as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at