ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.35del (p.Gly12fs) (rs80338939)

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Total submissions: 34
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel, RCV000211775 SCV000840537 pathogenic Nonsyndromic hearing loss and deafness 2018-09-20 reviewed by expert panel curation 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000844702 SCV000061505 pathogenic Rare genetic deafness 2018-03-01 criteria provided, single submitter clinical testing The c.35delG variant in GJB2 is known to be pathogenic with many supporting publ ications. ACMG/AMP Criteria applied: PVS1, PM3_VeryStrong.
Genetic Services Laboratory, University of Chicago RCV000146019 SCV000193171 pathogenic Hearing impairment 2013-02-08 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories,Oregon Health and Sciences University RCV000018527 SCV000223930 pathogenic Deafness, autosomal recessive 1A 2016-03-14 criteria provided, single submitter clinical testing 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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000080373 SCV000227317 pathogenic not provided 2016-01-04 criteria provided, single submitter clinical testing The c.35delG deletion is the most common pathogenic variant associated with hearing loss. Www.ncbi.nlm.nih.gov/books/NBK1272/1
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000080373 SCV000257945 pathogenic not provided 2015-11-16 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000080373 SCV000280697 pathogenic not provided 2014-11-24 criteria provided, single submitter clinical testing
GeneDx RCV000080373 SCV000321725 pathogenic not provided 2018-10-26 criteria provided, single submitter clinical testing The c.35delG variant in the GJB2 gene has been reported previously in association with autosomal recessive nonsyndromic hearing loss when present in the homozygous state or when in trans with another pathogenic variant (Kenneson et al., 2002). The c.35delG variant is the most common GJB2 pathogenic variant among individuals of European background (Gasparini et al., 2000), and the hearing loss present in individuals homozygous for the c.35delG variant ranges from mild to profound (Hilgert et al., 2009). Most individuals known to be heterozygous for the c.35delG variant have normal hearing, although subclinical differences in the otoacoustic emissions of carriers has been noted upon audiologic examination (Morell et al., 1998). The c.35delG variant causes a frameshift starting with codon Glycine 12, changes this amino acid to a Valine residue, and creates a premature Stop codon at position 2 of the new reading frame, denoted p.Gly12ValfsX2. This variant is predicted to cause loss of normal protein function through protein truncation. The c.35delG variant is observed in 1,207/124,552 alleles (0.97%) from individuals of non-Finnish European background in large population cohorts, including 10 homozygous individuals (Lek et al., 2016). In vitro studies demonstrate that the c.35delG variant results in a loss of connexin 26 function (D'Andrea et al., 2002). We interpret c.35delG as a pathogenic variant.
Counsyl RCV000018527 SCV000487401 pathogenic Deafness, autosomal recessive 1A 2016-03-08 criteria provided, single submitter clinical testing
Counsyl RCV000411531 SCV000487402 pathogenic Deafness, autosomal dominant 3a 2016-03-08 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415181 SCV000492685 pathogenic Bilateral sensorineural hearing impairment 2014-10-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000146019 SCV000492742 pathogenic Hearing impairment 2017-01-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415367 SCV000492743 pathogenic Hearing impairment; Bilateral conductive hearing impairment 2015-01-13 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000414886 SCV000492744 pathogenic Hearing impairment; Bilateral sensorineural hearing impairment 2014-04-12 criteria provided, single submitter clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000018527 SCV000599723 pathogenic Deafness, autosomal recessive 1A 2017-05-09 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000080373 SCV000603812 pathogenic not provided 2017-05-03 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000080373 SCV000613516 pathogenic not provided 2018-03-16 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000018527 SCV000698250 pathogenic Deafness, autosomal recessive 1A 2017-08-08 criteria provided, single submitter clinical testing 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.
Ambry Genetics RCV000623840 SCV000741869 pathogenic Inborn genetic diseases 2014-09-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000018527 SCV000746336 pathogenic Deafness, autosomal recessive 1A 2018-08-07 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000018527 SCV000915629 pathogenic Deafness, autosomal recessive 1A 2018-12-04 criteria provided, single submitter clinical testing 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.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens RCV000018527 SCV000928370 pathogenic Deafness, autosomal recessive 1A 2018-06-26 criteria provided, single submitter clinical testing PVS1, PS3, PM1, PP5
Invitae RCV000080373 SCV000950817 pathogenic not provided 2019-01-08 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gly12Valfs*2) in the GJB2 gene. It is expected to result in an absent or disrupted protein product. This variant has been reported to segregate with hearing loss in several families (PMID: 9285800, 9328482), and is considered to be a founder mutation in the European population (PMID: 10751669, 12172392, 12176036, 12239718, 19925344). ClinVar contains an entry for this variant (Variation ID: 17004). An experimental study has shown that this frameshift disrupts in GJB2 protein expression and function in cell culture (PMID: 12176036). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000018527 SCV000038809 pathogenic Deafness, autosomal recessive 1A 2012-10-05 no assertion criteria provided literature only
OMIM RCV000018528 SCV000038810 pathogenic Deafness, digenic, GJB2/GJB6 2012-10-05 no assertion criteria provided literature only
GeneReviews RCV000018527 SCV000041047 pathologic Deafness, autosomal recessive 1A 2011-07-14 no assertion criteria provided curation Converted during submission to Pathogenic.
Division of Human Genetics,Children's Hospital of Philadelphia RCV000018527 SCV000238466 pathogenic Deafness, autosomal recessive 1A 2015-03-20 no assertion criteria provided research 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).
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415175 SCV000492702 pathogenic Severe sensorineural hearing impairment 2016-01-04 no assertion criteria provided clinical testing
Division of Human Genetics,Children's Hospital of Philadelphia RCV000477882 SCV000536698 pathogenic Deafness, autosomal recessive 1A; Mutilating keratoderma; Hystrix-like ichthyosis with deafness; Keratitis-ichthyosis-deafness syndrome, autosomal dominant; Keratoderma palmoplantar deafness; Knuckle pads, deafness AND leukonychia syndrome; Deafness, autosomal dominant 3a 2014-10-31 no assertion criteria provided research
GenomeConnect, ClinGen RCV000509532 SCV000606924 not provided Deafness no assertion provided phenotyping only 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.
GenomeConnect, ClinGen RCV000509463 SCV000607350 not provided Nonsyndromic Hearing Loss, Recessive no assertion provided phenotyping only 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.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678860 SCV000805053 pathogenic Hearing loss 2017-02-22 no assertion criteria provided clinical testing
Center for Statistical Genetics, Columbia University RCV000146019 SCV000853303 pathogenic Hearing impairment 2018-11-22 no assertion criteria provided research
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery,Institute of Otolaryngology, Chinese PLA General Hospital RCV000018527 SCV000902318 pathogenic Deafness, autosomal recessive 1A 2019-02-26 no assertion criteria provided case-control

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