ClinVar Miner

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

gnomAD frequency: 0.00006  dbSNP: 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,Mass General Brigham Personalized Medicine RCV000211773 SCV000061497 pathogenic Rare genetic deafness 2006-10-28 criteria provided, single submitter clinical testing
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 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 Autosomal recessive nonsyndromic hearing loss 1A; Autosomal recessive nonsyndromic hearing loss 1B criteria provided, single submitter clinical testing
Myriad Women's Health, 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.
Invitae RCV000255698 SCV001234132 pathogenic not provided 2021-12-18 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 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 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 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

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