ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.-22-2A>C (rs201895089)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV000710316 SCV000840501 likely pathogenic Nonsyndromic hearing loss and deafness 2021-04-28 reviewed by expert panel curation NM_004004.6(GJB2):c.-22-2A>C- Likely Pathogenic, Marina The filtering allele frequency of the c.-22-2A>C variant in the GJB2 gene is 0.35% for Ashkenazi Jewish chromosomes in gnomAD (95% CI of 47/10344), which meets the allele frequency threshold defined by the ClinGen Hearing Loss Expert Panel for considering strong evidence against pathogenicity for autosomal recessive hearing loss variants (BS1). However, based on the evidence outlined below, the ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for nonsyndromic hearing loss outweighs its high allele frequency in population databases. Therefore, the BS1 code will not contribute to the overall classification. The c.-22-2A>C variant in the GJB2 gene has been detected in at least 9 patients with hearing loss in trans with the pathogenic c.35delG variant (PM3_Very Strong; PMID: 25401782, 24039984, 33096615; Invitae internal data, SCV000935680.2; Children’s Hospital of Philadelphia internal data, Molecular Otolaryngology and Renal Research Laboratories internal data) and one individual with the the p.Leu90Pro variant suspected in trans (PMID: 19814620). Phase was confirmed in at least 6 of these 10 observations.This variant has been reported to segregate with hearing loss in at least 2 family members (PP1; PMID: 24039984). It was also identified in the heterozygous state without a second variant in 8 individuals with hearing loss, and in the biallelic state (with c.35delG) in one individual with reportedly normal hearing (GeneDx, ARUP internal data, SCV000680741.2, SCV000603828.1). Of note, the severity of hearing loss is reported to be mild-moderate in affected probands, some with onset in the third to fourth decade, suggesting that this variant may be a hypomorphic allele. RNA analysis using patient cells demonstrated that the c.-22-2A>C variant leads to expression of a novel GJB2 transcript with a slightly longer 5' UTR but otherwise normal coding region. The alternate transcript was shown to have reduced expression, but it is not clear if the lower expression is sufficient to lead to a phenotype (PS3_Supporting; PMID: 24039984). In summary, this variant has been classified as likely pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM3_Very Strong, PP1, PS3_Supporting, BS1.
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000416425 SCV000494235 pathogenic Deafness, autosomal recessive 1A 2016-04-08 criteria provided, single submitter clinical testing The c.-22-2A>C splice-acceptor variant in the GJB2 gene has been previously reported in 3 individuals within one generation of a single family affected with Deafness and Hearing Loss (Gandía et al., 2013). In all cases, this variant was observed in trans with the well-established pathogenic variant 35delG; however, these individuals experienced mild to moderate hearing loss that developed in the 3rd-4th decade of life (postlingual) (Gandía et al., 2013). Functional splicing studies have demonstrated this variant abolishes the canonical splice-acceptor site for intron 1 of GJB2. The loss of the canonical splice-site results in a longer transcript caused by an alternative splice-acceptor site that is within intron 1(Gandía et al., 2013). This variant is reported at low frequency in the population databases (Exome Sequencing Project = 0.058%; 1000 Genomes = 0%; and ExAC = 0.114%). Therefore, this collective evidence supports the classification of the c.-22-2A>C as a Pathogenic variant for Deafness and Hearing Loss. We have confirmed this finding in our laboratory using Sanger sequencing.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000507029 SCV000603828 pathogenic not specified 2016-12-01 criteria provided, single submitter clinical testing
GeneDx RCV000579320 SCV000680741 uncertain significance not provided 2020-01-09 criteria provided, single submitter clinical testing Reported as a single heterozygous variant in an individual with hearing loss; however, a detailed clinical phenotype for this individual was not described (Burke et al., 2016); Published functional studies demonstrate two alternative cryptic splice acceptor sites were activated in lieu of the destroyed canonical splice acceptor site in intron 1 due to this variant (Gandia et al., 2013). While usage of these alternative splice acceptor sites are predicted to alter the untranslated regions of this transcript, the regions encoding the GJB2 protein remain intact.; This variant is associated with the following publications: (PMID: 31053783, 24039984, 26778469, 29016196, 30455902, 30311386, 29754767, 31980526, 33096615)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000416425 SCV000698235 likely pathogenic Deafness, autosomal recessive 1A 2021-11-01 criteria provided, single submitter clinical testing Variant summary: GJB2 c.-22-2A>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes the canonical 3' acceptor site. At least one publication reports experimental evidence that this variant leads to alternative splicing and two novel transcripts which may express some level of wild type GJB2 (Gandia_2013). However, the tissue type used in this study, saliva, may not represent the most optimal tissue type to base evidence supporting residual transcript expression in an affected tissue. A cochlear tissue, or another ear expressed tissue type may be more informative. The variant allele was found at a frequency of 0.00061 in 251058 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in GJB2 causing Autosomal Recessive Non-Syndromic Hearing Loss (0.00061 vs 0.025), allowing no conclusion about variant significance. c.-22-2A>C has been reported in the literature as a compound heterozygous genotype with c.35delG in individuals predominantly reported to have postlingual mild-moderate hearing loss (example, Gandia_2013, Burke_2016, Stanghellini_2014, Cabanillas_2018, Buonfigilio_2020). Although one conference abstract showed that there was no significant difference in allelic or genotypic frequencies between patient and control groups in an Italian subpopulation, the authors did state that the disease-causing effect of this variant when in trans with a truncating mutation cannot be excluded (Gandia_2013). Furthermore, at-least one recent study re-evaluated this variant as "Likely Pathogenic" reporting the ACMG/AMP criteria coupled with hearing-loss-gene-specific criteria of the ClinGen hearing loss expert panel (Buonfigilio_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge no direct experimental evidence evaaluating a variant specific impact on protein function and assembly have been reported. Multiple clinical diagnostic laboratories and an expert panel (ClinGen Hearing Loss Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple submitters reported the variant with conflicting assessments (Pathogenic, n=2; Likely pathogenic, n=2; Benign, n=1; Likely benign, n=1, VUS, n=4 to include the expert panel). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic for postlingual mild-moderate hearing loss.
Illumina Clinical Services Laboratory,Illumina RCV000416425 SCV000915630 likely pathogenic Deafness, autosomal recessive 1A 2018-08-16 criteria provided, single submitter clinical testing The GJB2 c.-22-2A>C variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.-22-2A>C variant has been identified in a compound heterozygous state in four individuals with hearing loss. Three of these individuals were from a single Spanish family and exhibited mild, postlingual hearing impairment, with onset in the third to fourth decade of life (Gandía et al. 2013). The fourth individual was of Italian origin and displayed moderate hearing impairment of unspecified onset (Stanghellini et al. 2014). In all four cases, the c.-22-2A>C variant was found in trans with a well-known pathogenic null variant, c.35delG. The Spanish pedigree also included two normal hearing heterozygous individuals, consistent with a recessive pattern of inheritance. The variant was absent from 92 normal hearing control individuals and is reported at a frequency of 0.004539 in the Ashkenazi Jewish population of the Genome Aggregation Consortium. Quantitative RT-PCR experiments indicated that the variant abolishes the canonical acceptor splice site for intron 1 of GJB2 but that a reduced amount of transcript is produced via an alternative acceptor splice site (Gandía et al. 2013). Based on the evidence, the c.-22-2A>C allele is classified as likely pathogenic for autosomal recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000579320 SCV000935680 likely benign not provided 2020-12-08 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001109959 SCV001267343 benign Hystrix-like ichthyosis with deafness 2017-08-23 criteria provided, single submitter clinical testing 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Clinical Services Laboratory,Illumina RCV001109960 SCV001267344 benign Deafness, autosomal dominant 3a 2017-08-23 criteria provided, single submitter clinical testing 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
INGEBI, INGEBI / CONICET RCV000710316 SCV001433672 likely pathogenic Nonsyndromic hearing loss and deafness 2020-08-31 criteria provided, single submitter clinical testing Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the filtering allele frequency of the c.-22-2A>C variant in the GJB2 gene is 0.35% (of 47/10344 alleles Ashkenazi Jewish with chromosomes with 95% CI) from Genome Aggregation Database calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/),applying to BS1 rule. The c.-22-2A>C variant has been detected in at least 4 patients with hearing loss in trans with the pathogenic c.35delG variant (PMID: 25401782, 24039984; Invitae internal data, SCV000935680.2; Laboratory of Physiology and Genetics of Hearing internal data described by ClinGen HL-EP). In addition to this, new evidence is considered since the c.-22-2A>C variant was reported in trans with p.Leu90Pro in a hearing impaired patient (PMID: 19814620, nomenclature issue checked with author: the variant called c.-24A>C in that paper is indeed c.-22-2A>C). In all those genotypes detected, patients exhibited postlingual mild-moderate hearing loss. Since this variant has a high frequency in population databases, the strength of PM3 rule was downgraded from very strong to moderate (PM3_Moderate). The c.[-22-2A>C];[35delG] genotype segregated in two affected and two unaffected members of the family (PP1_Strong; PMID: 24039984). RNA analysis showed that patients with the c.-22-2A>C variant used two alternative splice sites leading to slightly longer 5' UTR transcripts containing normal coding region but with alternated expression. This variant is suspected to be a hypomorphic allele resulting in a postlingual mild-moderate hearing loss phenotype (PS3_Supporting; PMID: 24039984). Therefore, this variant meets criteria to be classified as likely pathogenic for autosomal recessive non-syndromic hearing loss (BS1, PM3_Moderate, PP1_Strong, PS3_Supporting).
Neurogenetic Laboratory,Second Faculty of Medicine, Charles University RCV000416425 SCV001571591 uncertain significance Deafness, autosomal recessive 1A 2021-03-30 criteria provided, single submitter clinical testing
Counsyl RCV000416425 SCV001132402 uncertain significance Deafness, autosomal recessive 1A 2019-04-01 no assertion criteria provided clinical testing

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