ClinVar Miner

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

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000507029 SCV000603828 pathogenic not specified 2016-12-01 criteria provided, single submitter clinical testing
ClinGen Hearing Loss Variant Curation Expert Panel, RCV000710316 SCV000840501 uncertain significance Nonsyndromic hearing loss and deafness 2018-10-25 reviewed by expert panel curation The filtering allele frequency of the c.-22-2A>C variant in the GJB2 gene is 0.35% for Ashkenazi Jewish chromosomes in the Genome Aggregation Database (46/10134 with 95% CI), 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, the c.-22-2A>C variant in the GJB2 gene has been detected in 2 patients with hearing loss in trans with the pathogenic c.35delG variant (PM3_S; PMID: 25401782, 24039984). This variant has been reported to segregate with hearing loss in at least 2 family members (PP1_M; PMID: 24039984). It was also identified in the heterozygous state without a second variant in 4 individuals with hearing loss, and in the biallelic state (with 35delG) in one individual with reportedly normal hearing (GeneDx, ARUP, unpublished data). RNA analysis showed that patients with the -22-2A>C variant express 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, due to its high allele frequency, insufficient case observations and insufficient functional evidence, this variant has been classified as uncertain clinical significance for autosomal recessive hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM3_Supporting, PP1_Moderate, PS3_Supporting, BS1
GeneDx RCV000579320 SCV000680741 uncertain significance not provided 2018-03-28 criteria provided, single submitter clinical testing The c.-21-2A>C variant in the GJB2 gene has been reported previously in three siblings with postlingual hearing loss who also harbored the c.35delG pathogenic variant on the opposite allele (Gandia et al., 2013). The c.-21-2A>C variant was also 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). The c.-21-2A>C variant is observed in 76/66386 (0.11%) alleles from individuals of non-Finnish European background in large population cohorts, with no homozygotes reported (Lek et al., 2016). Functional studies demonstrated 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. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
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.
Integrated Genetics/Laboratory Corporation of America RCV000416425 SCV000698235 pathogenic Deafness, autosomal recessive 1A 2018-04-12 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 a 3 prime 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). The variant allele was found at a frequency of 0.00068 in 123170 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in GJB2 causing Autosomal Recessive Non-Syndromic Hearing Loss (0.00068 vs 0.025), allowing no conclusion about variant significance. c.-22-2A>C has been reported in the literature in individuals affected with Autosomal Recessive Non-Syndromic Hearing Loss in compound heterozygous state with c.35delG (Gandia_2013 and Stanghellini_2014). 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). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000579320 SCV000935680 likely pathogenic not provided 2018-12-26 criteria provided, single submitter clinical testing This sequence change falls in intron 1 of the GJB2 gene. It does not directly change the encoded amino acid sequence of the GJB2 protein. This variant is present in population databases (rs201895089, ExAC 0.1%). This variant has been observed in compound heterozygous state with c.35delG (p.Gly12Valfs*2) to segregate with post-lingual hearing loss in one family (PMID: 24039984). ClinVar contains an entry for this variant (Variation ID: 375406). Experimental studies have shown that this splice acceptor change abolishes transcription from the canonical acceptor site and results in production of a smaller transcript from an alternate splice acceptor site with reduced levels of GJB2 transcripts (PMID: 24039984). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
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.

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