ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.299_300del (p.His100fs) (rs111033204)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000211773 SCV000061497 pathogenic Rare genetic deafness 2006-10-28 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000255698 SCV000227303 pathogenic not provided 2014-09-18 criteria provided, single submitter clinical testing
GeneDx RCV000255698 SCV000322425 pathogenic not provided 2018-10-23 criteria provided, single submitter clinical testing The c.299_300delAT variant in the GJB2 gene has been reported previously in association with nonsyndrome hearing loss, and is a common variant seen with hearing loss in the Chinese population (Li et al., 2014; Huang et al., 2013; Abe et al., 2000). The c.299_300delAT variant causes a frameshift starting with codon Histidine 100, changes this amino acid to an Arginine residue, and creates a premature Stop codon at position 14 of the new reading frame, denoted p.His100ArgfsX14. This variant is predicted to cause loss of normal protein function through protein truncation. Functional studies show c.299_300delAT protein is retained in the endoplasmic reticulum and cannot form gap junctions in the plasma membrane (Zhang et al., 2010). The variant is observed in 17/18868 (0.09%) alleles from individuals of East Asian background in large population cohorts (Lek et al., 2016). We interpret c.299_300delAT as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000037835 SCV000917454 pathogenic Deafness, autosomal recessive 1A 2018-02-23 criteria provided, single submitter clinical testing Variant summary: GJB2 c.299_300delAT (p.His100ArgfsX14) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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 (eg. c.313_326delAAGTTCATCAAGGG, p.Lys105fsX5; c.334_335delAA, p.Lys112fsX2; c.370C>T, p.Gln124X). The variant allele was found at a frequency of 7.2e-05 in 277508 control chromosomes (gnomAD and literature). This frequency is not higher than expected for a pathogenic variant in GJB2 causing Non-Syndromic Hearing Loss (7.2e-05 vs 2.60e-02), allowing no conclusion about variant significance. The c.299_300delAT variant has been reported in the literature in numerous individuals affected with Non-Syndromic Hearing Loss (Dai_2009, Hismi_2006, Abe_2000), in both compound heterozygotes and homozygotes. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Athena Diagnostics Inc RCV000255698 SCV001143665 pathogenic not provided 2018-12-04 criteria provided, single submitter clinical testing The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001373 SCV001158571 pathogenic not specified 2019-06-28 criteria provided, single submitter clinical testing The GJB2 c.299_300delAT; p.His100fs variant (rs111033204) is reported in the literature in multiple individuals affected with nonsyndromic hearing loss (Abe 2000, Chen 2016, Huang 2013, Wang 2002). Several affected individuals with this variant were also observed to carry a second pathogenic variant (Abe 2000, Huang 2013, Wang 2002), including two siblings confirmed to carry another frameshift variant in trans to p.His100fs (Wang 2002). This variant is found in the East Asian population with an overall allele frequency of 0.09% (18/19950 alleles) in the Genome Aggregation Database, and it is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 44736). This variant causes a frameshift by deleting two nucleotides, 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: Abe S et al. Prevalent connexin 26 gene (GJB2) mutations in Japanese. J Med Genet. 2000 Jan;37(1):41-3. Chen K et al. GJB2 and mitochondrial 12S rRNA susceptibility mutations in sudden deafness. Eur Arch Otorhinolaryngol. 2016 Jun;273(6):1393-8. Huang S et al. Identification of a p.R143Q dominant mutation in the gap junction beta-2 gene in three Chinese patients with different hearing phenotypes. Acta Otolaryngol. 2013 Jan;133(1):55-8. Wang YC et al. Mutations of Cx26 gene (GJB2) for prelingual deafness in Taiwan. Eur J Hum Genet. 2002 Aug;10(8):495-8.
Baylor Genetics RCV001004390 SCV001163362 pathogenic Deafness, autosomal recessive 1A; Deafness, autosomal recessive 1b criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000037835 SCV001194101 pathogenic Deafness, autosomal recessive 1A 2019-12-20 criteria provided, single submitter clinical testing NM_004004.5(GJB2):c.299_300delAT(H100Rfs*14) is classified as pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. Sources cited for classification include the following: PMID 20095872 and 19366456. Classification of NM_004004.5(GJB2):c.299_300delAT(H100Rfs*14) 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 RCV000255698 SCV001234132 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.His100Argfs*14). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 127 amino acids of the GJB2 protein. This variant is present in population databases (rs111033204, ExAC 0.06%). This variant has been observed to be homozygous or in combination with another GJB2 variant in individuals affected with deafness (PMID: 22991996, 26043044, 24341454, 10633133, 12111646, 27610647, 20083784). ClinVar contains an entry for this variant (Variation ID: 44736). This variant has been reported to affect GJB2 protein function (PMID: 20095872). This variant disrupts the p.Asn206 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been observed in individuals with GJB2-related conditions (PMID: 12172394, 14985372, 15070423, 15967879), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000255698 SCV001449535 pathogenic not provided 2019-10-02 criteria provided, single submitter clinical testing
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery,Institute of Otolaryngology, Chinese PLA General Hospital RCV000037835 SCV000902317 pathogenic Deafness, autosomal recessive 1A 2019-02-26 no assertion criteria provided case-control
Natera, Inc. RCV000037835 SCV001453339 pathogenic Deafness, autosomal recessive 1A 2020-09-16 no assertion criteria provided clinical testing

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