ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.313_326del (p.Lys105fs) (rs111033253)

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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000211774 SCV000061498 pathogenic Rare genetic deafness 2017-05-04 criteria provided, single submitter clinical testing The p.Lys105fs variant in GJB2 is a well-known pathogenic variant and has been i dentified in many individuals with hearing loss who were homozygous or compound heterozygous with another pathogenic variant in GJB2 (Marlin 2005). It has been reported in 27/126134 European chromosomes and 10/20780 South Asian chromosomes by the Genome Aggregation Database (; dbSNP rs1 99976861). This frequency in the general population is consistent with the carri er frequency for autosomal recessive hearing loss. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 105 and leads to a premature termination codon 5 amino acids downstream . In summary, this variant meets criteria to be classified as pathogenic for aut osomal recessive hearing loss based on the predicted impact to the protein and m ultiple previously reported affected compound heterozygotes. ACMG/AMP Criteria a pplied: PVS1, PM3_VeryStrong.
Genetic Services Laboratory,University of Chicago RCV000146016 SCV000193167 pathogenic Hearing impairment 2013-02-08 criteria provided, single submitter clinical testing
GeneDx RCV000080370 SCV000329860 pathogenic not provided 2018-07-24 criteria provided, single submitter clinical testing The c.313_326del14 pathogenic variant in the GJB2 gene, also reported as 312del14, has been reported previously in the homozygous state, compound heterozygous with a second GJB2 variant, or as the only identified variant in patients with nonsyndromic hearing loss (Denoyelle et al., 1999; Danilenko et al., 2012; Miksteiene et al., 2016; Barashkov et al., 2016). The deletion causes a frameshift starting with codon Lysine 105, changes this amino acid to a Glycine residue and creates a premature Stop codon at position 5 of the new reading frame, denoted p.Lys105GlyfsX5. This pathogenic variant is predicted to cause loss of normal protein function through protein truncation, as the last 122 amino acids are replaced by 4 aberrant amino acids. The c.313_326del14 variant is observed in 10/30780 (0.033%) alleles from individuals of South Asian background in large population cohorts (Lek et al., 2016). Therefore, we interpret the c.313_326del14 variant as pathogenic.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000146016 SCV000492741 pathogenic Hearing impairment 2015-01-13 criteria provided, single submitter clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000037836 SCV000599744 pathogenic Deafness, autosomal recessive 1A 2017-05-09 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000506547 SCV000603830 pathogenic none provided 2020-01-10 criteria provided, single submitter clinical testing The GJB2 c.313_326del; p.Lys105fs variant (rs111033253) is reported in the literature in individuals affected with hearing loss, both in the homozygous state and in trans to other pathogenic variants (Dalamon 2013, Denoyelle 1999, Kupa 2002, Mikstiene 2016). This variant is reported as pathogenic by numerous laboratories in ClinVar (Variation ID: 44737) and it is found in the general population with an overall allele frequency of 0.01% (38/281690 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting 14 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, the c.313_326del variant is considered to be pathogenic. References: Dalamon V et al. Identification of four novel connexin 26 mutations in non-syndromic deaf patients: genotype-phenotype analysis in moderate cases. Mol Biol Rep. 2013 Dec;40(12):6945-55. Denoyelle F et al. Clinical features of the prevalent form of childhood deafness, DFNB1, due to a connexin-26 gene defect: implications for genetic counselling. Lancet. 1999 Apr 17;353(9161):1298-303. Kupka S et al. Frequencies of GJB2 mutations in German control individuals and patients showing sporadic non-syndromic hearing impairment. Hum Mutat. 2002 Jul;20(1):77-8. Mikstiene V et al. The high frequency of GJB2 gene mutation c.313_326del14 suggests its possible origin in ancestors of Lithuanian population. BMC Genet. 2016 Feb 19;17:45.
Athena Diagnostics Inc RCV000080370 SCV000613512 pathogenic not provided 2017-03-06 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000037836 SCV000698245 pathogenic Deafness, autosomal recessive 1A 2016-11-18 criteria provided, single submitter clinical testing Variant summary: The GJB2 c.313_326delAAGTTCATCAAGGG (p.Lys105Glyfs) variant (alternatively also known as 313del14, 313-326del14, or 312del14) results in a premature termination codon, predicted to cause a truncated or absent GJB2 protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. If NMD is escaped, this variant is expected to truncate gap junction protein, cysteine-rich domain and connexin, N-terminal domain (InterPro).Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Gln124X, p.Gln164X, c.647_650delGAGA, etc.). This variant was found in 12/121692 control chromosomes at a frequency of 0.0000986, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). This variant is recurrently reported in patients with autosomal recessive NSHL and is reported to have hearing loss less severe than the c.35delG homozygotes (Kupka_2002, Wu_2002, Cryns_2004, Marlin_2005). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000080370 SCV000700403 pathogenic not provided 2015-02-11 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000037836 SCV000914614 pathogenic Deafness, autosomal recessive 1A 2018-08-15 criteria provided, single submitter clinical testing The GJB2 c.313_326delAAGTTCATCAAGGG (p.Lys105GlyfsTer5) variant results in a frameshift and is predicted to result in premature termination of the protein. Across a selection of the available literature, the p.Lys105GlyfsTer5 variant has been identified in a total of 59 individuals with autosomal recessive nonsyndromic hearing loss including 18 homozygotes and 41 compound heterozygotes (Denoyelle et al. 1999; Marlin et al. 2005; Bazazzadegan et al 2012; Mikstiene et al. 2016). Thirty-seven of the compound heterozygotes carry c.35delG, a well known pathogenic variant, on the second allele. The p.Lys105GlyfsTer5 variant was found in a heterozygous state in two control individuals and is reported at a frequency of 0.00032 in the South Asian population of the Genome Aggregation Database. Based on the collective evidence and potential impact of frameshift variants, the p.Lys105GlyfsTer5 variant is classified as pathogenic for autosomal recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Baylor Genetics RCV001004389 SCV001163361 pathogenic Deafness, autosomal recessive 1A; Deafness, autosomal recessive 1b criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000037836 SCV001194006 pathogenic Deafness, autosomal recessive 1A 2019-12-26 criteria provided, single submitter clinical testing NM_004004.5(GJB2):c.313_326del14(K105Gfs*5) is classified as pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. Sources cited for classification include the following: PMID 22567152. Classification of NM_004004.5(GJB2):c.313_326del14(K105Gfs*5) 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.
Invitae RCV000080370 SCV001227363 pathogenic not provided 2019-12-05 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the GJB2 gene (p.Lys105Glyfs*5). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 122 amino acids of the GJB2 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed to be homozygous or in combination with another GJB2 variant in individuals affected with deafness (PMID: 26896187, 22567152, 10218527, 27224056). ClinVar contains an entry for this variant (Variation ID: 44737). This variant disrupts the p.Pro173 and p.Arg184 amino acid residues in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15855033, 10982180, 10874298, 25708704, 25708704). This suggests that these residues are clinically-significant, and that variants that disrupt these residues are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000080370 SCV001245650 pathogenic not provided 2019-12-01 criteria provided, single submitter clinical testing
INGEBI, INGEBI / CONICET RCV001257561 SCV001434015 pathogenic Nonsyndromic hearing loss and deafness 2020-08-21 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.313_326del (p.Lys105fs*5) variant in the GJB2 gene is 0,015% (9/30614 South Asian alleles with 95% CI) in Genome Aggregation Database (; calculated by using inverse allele frequency at, which meets the PM2_Supporting criteria. The c.313_326del variant is predicted to cause a premature stop codon in the only exon of GJB2 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 trans with at least 4 pathogenic variants in different hearing loss patients (PMID: 10218527, 10982180, 11551103, 24158611, 27224056) applying to PM3_VeryStrong. This variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss: PM2_Supporting, PVS1, PM3_VeryStrong.
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000080370 SCV001449875 pathogenic not provided 2017-01-13 criteria provided, single submitter clinical testing
Department of Otolaryngology – Head & Neck Surgery,Cochlear Implant Center RCV000146016 SCV001571779 pathogenic Hearing impairment 2021-04-12 criteria provided, single submitter clinical testing PVS1_Strong, PS3_Strong, PP3_Supporting
OMIM RCV000037836 SCV000038814 pathogenic Deafness, autosomal recessive 1A 2004-08-01 no assertion criteria provided literature only
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678878 SCV000805071 pathogenic Hearing loss 2014-11-13 no assertion criteria provided clinical testing
Natera, Inc. RCV000037836 SCV001453338 pathogenic Deafness, autosomal recessive 1A 2020-09-16 no assertion criteria provided clinical testing

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