ClinVar Miner

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

gnomAD frequency: 0.00003  dbSNP: rs111033204
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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000211773 SCV000061497 pathogenic Rare genetic deafness 2019-08-12 criteria provided, single submitter clinical testing The His100fs variant in GJB2 has been previously reported in several individuals with hearing loss who were homozygous or compound heterozygous (Abe 2000, Bayazit 2003, Gabriel 2001, Park 2000, Snoeckx 2005, Wang 2002, Zhang 2010, LMM unpublished data). This variant has also been identified in 0.09% (18/19950) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frameshift variant is predicted to alter the protein’s amino acid sequence beginning at position 100 and lead to a premature termination codon 14 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the GJB2 gene is an established disease mechanism in autosomal recessive hearing loss. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss. ACMG/AMP Criteria applied: PVS1, PM3, PM2_Supporting.
Eurofins Ntd Llc (ga) RCV000255698 SCV000227303 pathogenic not provided 2014-09-18 criteria provided, single submitter clinical testing
GeneDx RCV000255698 SCV000322425 pathogenic not provided 2022-06-01 criteria provided, single submitter clinical testing Published functional studies demonstrate the protein is retained in the endoplasmic reticulum and cannot form gap junctions in the plasma membrane (Zhang et al., 2010); Frameshift variant predicted to result in protein truncation, as the last 127 amino acids are lost and replaced with 13 incorrect amino acids, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 29234782, 10983956, 30693673, 31160754, 25266519, 19043807, 26119842, 16380907, 11438992, 11385713, 12111646, 22695344, 19366456, 10633133, 30589569, 30282152, 31195736, 30036422, 31347505, 30146550, 31564438, 29625052, 26689913, 31541171, 30275481, 32645618, 33726816, 33597575, 29871260, 22875492, 32973888, 20095872, 22991996)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000037835 SCV000917454 pathogenic Autosomal recessive nonsyndromic hearing loss 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 RCV000255698 SCV001143665 pathogenic not provided 2022-03-15 criteria provided, single submitter clinical testing This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with autosomal recessive nonsyndromic hearing loss and deafness. Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiments showed mutant proteins were retained in the endoplasmic reticulum (ER) and thus unable to form gap junctions in the plasma membrane (PMID: 20095872).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000255698 SCV001158571 pathogenic not provided 2022-07-01 criteria provided, single submitter clinical testing The GJB2 c.299_300delAT; p.His100ArgfsTer14 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.His100ArgfsTer14 (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. PMID: 10633133. Chen K et al. GJB2 and mitochondrial 12S rRNA susceptibility mutations in sudden deafness. Eur Arch Otorhinolaryngol. 2016 Jun;273(6):1393-8. PMID: 26119842. 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. PMID: 22991996. Wang YC et al. Mutations of Cx26 gene (GJB2) for prelingual deafness in Taiwan. Eur J Hum Genet. 2002 Aug;10(8):495-8. PMID: 12111646.
Baylor Genetics RCV001004390 SCV001163362 pathogenic Autosomal recessive nonsyndromic hearing loss 1A; Autosomal recessive nonsyndromic hearing loss 1B criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV000037835 SCV001194101 pathogenic Autosomal recessive nonsyndromic hearing loss 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000255698 SCV001234132 pathogenic not provided 2024-01-16 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.His100Argfs*14) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 127 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs111033204, gnomAD 0.09%). This premature translational stop signal has been observed in individuals with autosomal recessive deafness (PMID: 10633133, 12111646, 20083784, 22991996, 24341454, 26043044, 27610647). ClinVar contains an entry for this variant (Variation ID: 44736). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects GJB2 function (PMID: 20095872). This variant disrupts the p.Asn206 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12172394, 14985372, 15070423, 15967879). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital RCV000255698 SCV001449535 pathogenic not provided 2019-10-02 criteria provided, single submitter clinical testing
MGZ Medical Genetics Center RCV000037835 SCV002579951 pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2022-05-17 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002496601 SCV002805215 pathogenic Autosomal recessive nonsyndromic hearing loss 1A; Mutilating keratoderma; Ichthyosis, hystrix-like, with hearing loss; Autosomal dominant keratitis-ichthyosis-hearing loss syndrome; Palmoplantar keratoderma-deafness syndrome; Knuckle pads, deafness AND leukonychia syndrome; Autosomal dominant nonsyndromic hearing loss 3A; X-linked mixed hearing loss with perilymphatic gusher 2021-08-19 criteria provided, single submitter clinical testing
Integrating Genomics into Medicine, Frazer Institute, University Of Queensland RCV000037835 SCV003935283 pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2023-06-02 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 Autosomal recessive nonsyndromic hearing loss 1A 2019-02-26 no assertion criteria provided case-control
Natera, Inc. RCV000037835 SCV001453339 pathogenic Autosomal recessive nonsyndromic hearing loss 1A 2020-09-16 no assertion criteria provided clinical testing
Gene Friend Way, National Innovation Center RCV003313933 SCV004013886 pathogenic Autism spectrum disorder 2023-07-28 no assertion criteria provided clinical testing Carriers of this GJB2 His100fs mutation in our study were diagnosed with ASD with little or no responses when called. Harmful mutation in the GJB2 genes were previously reported to associated with nonsyndromic hearing loss (Bartolotta et al., 2014, Wei et al., 2014).

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