ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.167del (p.Leu56fs) (rs80338942)

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Total submissions: 25
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV000211757 SCV000840535 pathogenic Nonsyndromic hearing loss and deafness 2018-09-19 reviewed by expert panel curation The filtering allele frequency of the p.Leu56ArgfsX26 variant in the GJB2 gene is 1.4% (165/10106) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), 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 nonsyndromic hearing loss variants (BA1). The ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for nonsyndromic hearing loss outweighs the high allele frequency of the variant in population databases. Therefore, the BA1 code will not contribute to the overall classification. The p.Leu56ArgfsX26 variant in GJB2 is predicted to cause a premature stop codon in the only coding exon of the gene, leading to an absent protein in a gene in which loss-of-function is an established disease 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: 24529908, 26096904, 24158611, 9285800, 17666888). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PVS1, PM3_VS, BA1.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000844699 SCV000061479 pathogenic Rare genetic deafness 2011-12-08 criteria provided, single submitter clinical testing The c.167delT variant in GJB2 is known to be pathogenic with many supporting pub lications. PVS1, PM3_VeryStrong.
Genetic Services Laboratory,University of Chicago RCV000146010 SCV000193161 pathogenic Hearing impairment 2013-02-08 criteria provided, single submitter clinical testing
GeneDx RCV000255988 SCV000321727 pathogenic not provided 2018-08-07 criteria provided, single submitter clinical testing The c.167delT variant in the GJB2 gene has been reported previously in association with non-syndromic autosomal recessive hearing loss when present in the homozygous state or when in trans with another pathogenic variant (Zelante et al., 1997; Morrell et al., 1998; Lerer et al., 2001). Most individuals known to be heterozygous for the c.167delT 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.167delT variant causes a frameshift starting with codon Leucine 56, changes this amino acid to an Arginine residue, and creates a premature Stop codon at position 26 of the new reading frame, denoted p.Leu56ArgfsX26. This variant is predicted to cause loss of normal protein function through protein truncation. We interpret c.167delT as a pathogenic variant.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000255988 SCV000330926 pathogenic not provided 2015-07-30 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000392361 SCV000383030 likely benign Hystrix-like ichthyosis with deafness 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000291910 SCV000383031 likely benign Mutilating keratoderma 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000346888 SCV000383032 pathogenic GJB2-Related Disorders 2018-05-16 criteria provided, single submitter clinical testing The GJB2 c.167delT (p.Leu56ArgfsTer26) variant results in a frameshift and is predicted to result in premature truncation of the protein. The p.Leu56ArgfsTer26 variant is a well-known variant that is common in the Ashkenazi Jewish population, where the carrier rate is as high as 7.5% (Lerer et al. 2000). Across a selection of the available literature, the p.Leu56ArgfsTer26 variant has been identified in a total of 34 patients with autosomal recessive nonsyndromic hearing loss, including in 16 in a homozygous state, in 15 in a compound heterozygous state, and in three in a heterozygous state (Zelante et al. 1997; Morell et al. 1998; Lerer et al. 2000; Batissoco et al. 2009; Bonyadi et al. 2014; Amorini et al. 2015). The p.Leu56ArgfsTer26 variant was shown to segregate with disease in at least one family. Patients with this variant show a spectrum of phenotypic manifestation from mild to profound hearing loss, even among affected family members (Morell et al. 1998). Control data is unavailable for this variant, which is reported at a frequency of 0.00145 in the European-American population of the Exome Sequencing Project (Morell et al. 1998; Lerer et al. 2000). Based on the collective evidence and the potential impact of frameshift variants, the p.Leu56ArgfsTer26 variant is classified as pathogenic for GJB2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Illumina Clinical Services Laboratory,Illumina RCV000392353 SCV000383033 likely benign Keratitis ichthyosis and deafness syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000307189 SCV000383034 likely benign Nonsyndromic Hearing Loss, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Counsyl RCV000409300 SCV000487400 pathogenic Deafness, autosomal dominant 3a 2015-12-18 criteria provided, single submitter clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000018534 SCV000599734 pathogenic Deafness, autosomal recessive 1A 2017-05-09 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000255988 SCV000613506 pathogenic not provided 2017-01-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000018534 SCV000698231 pathogenic Deafness, autosomal recessive 1A 2017-08-25 criteria provided, single submitter clinical testing Variant summary: The c.167delT variant results in a premature termination codon, predicted to cause a truncated or absent GJB2 protein, which is a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.269dupT, c.313_326del, c.647_650delGATA, etc.). This variant was found in 84/123144 control chromosomes (3 homozygotes) at a frequency of 0.0006821, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). This variant is a well-known common pathogenic variant predominantly found in Ashkenazi Jewish population. In addition, multiple clinical laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant has been classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000255988 SCV000883944 pathogenic not provided 2017-05-09 criteria provided, single submitter clinical testing The GJB2 c.167delT; p.Leu56fs variant (rs80338942) creates a frameshift and is predicted to result in a truncated protein or absent transcript. Homozygous and compound heterozygous c.167delT variants have been reported in a number of patients with hearing loss (Kenna 2010, Snoeckx 2005). This variant is reported to ClinVar (Variation ID: 17010), and observed in the general population databases with an overall allele frequency of 0.08 percent (218/276720 alleles), including 3 homozygotes (Genome Aggregation Database). Importantly, this variant has been reported at a carrier frequency of 2.4-7.5 percent in Ashkenazi Jewish individuals (Bors 2004, Lerer 2000, Morell 1998, Sobe 1999). Taken together, this variant is considered pathogenic. REFERENCES Link to ClinVar database for c.167delT: https://www.ncbi.nlm.nih.gov/clinvar/variation/17010/ Bors A. et al. Frequencies of two common mutations (c.35delG and c.167delT) of the connexin 26 gene in different populations of Hungary. Int J Mol Med. 2004; 14(6):1105-1108. Gualandi F et al. Exploring the clinical and epidemiological complexity of GJB2-linked deafness. Am J Med Genet. 2002 Sep 15;112(1):38-45. Kenna MA et al. Audiologic Phenotype and Progression in GJB2 (Connexin 26) Hearing Loss. Arch Otolaryngol Head Neck Surg 2010; 136(1):81-87. Lerer I et al. Contribution of connexin 26 mutations in non-syndromic deafness in Ashkenazi patients and the variable phenotypic effect of the mutation 167delT. Am. J. Med. Genet. 2000; 95:53-56. Morell RJ et al. Mutations in the connexin 26 gene (GJB2) among Ashkenazi Jews with nonsyndromic recessive deafness. N Engl J Med. 1998; 339(21):1500-1505. Snoeckx RL et al. GJB2 Mutations and Degree of Hearing Loss: A Multicenter Study. Am J Hum Genet 2005; 77:945-957. Sobe T et al. High frequency of the deafness-associated 167delT mutation in the connexin 26 (GJB2) gene in Israeli Ashkenazim. Am J Med Genet. 1999; 86:499-500.
Invitae RCV000255988 SCV000940600 pathogenic not provided 2019-12-30 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the GJB2 gene (p.Leu56Argfs*26). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 171 amino acids of the GJB2 protein. This variant is present in population databases (rs80338942, ExAC 0.1%). This variant has been observed to be homozygous or in combination with another GJB2 variant in individuals affected with nonsyndromic hearing loss (PMID: 15967879, 16380907, 21465647, 22695344, 24158611), and has been shown to segregate with disease in several families (PMID: 9819448, 10982182, 11935342) and is considered to be a founder mutation in the Ashkenazi Jewish population (PMID: 9819448). ClinVar contains an entry for this variant (Variation ID: 17010). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001002181 SCV001160051 pathogenic not specified 2019-05-30 criteria provided, single submitter clinical testing
Baylor Genetics RCV001004395 SCV001163367 pathogenic Deafness, autosomal recessive 1A; Deafness, autosomal recessive 1b criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000018534 SCV001193832 pathogenic Deafness, autosomal recessive 1A 2019-10-18 criteria provided, single submitter clinical testing NM_004004.5(GJB2):c.167delT(L56Rfs*26) is classified as pathogenic in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. Please note that L56Rfs*26 is associated with a variable presentation, ranging from mild to profound hearing loss. Sources cited for classification include the following: PMID 24158611, 10049954, 16380907, 10596881, 11556849, 11074495, and 10982182. Classification of NM_004004.5(GJB2):c.167delT(L56Rfs*26) 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.
Victorian Clinical Genetics Services,Murdoch Childrens Research Institute RCV000018534 SCV001244780 pathogenic Deafness, autosomal recessive 1A 2017-10-04 criteria provided, single submitter clinical testing A heterozygous deletion variant was identified, NM_004004.5(GJB2):c.167delT in exon 2 of the GJB2 gene.This deletion creates a frameshift from amino acid position 56, introducing a stop codon 26 residues downstream, NP_003995.2(GJB2):p.(Leu56Argfs*26). This is predicted to result in loss of protein function through truncation (>50% of the protein).This variant is present in the gnomAD population database at a frequency of 0.08% (218 heterozygotes, 3 homozygotes). It has been previously reported to be a common pathogenic variant in patients with autosomal recessive nonsyndromic hearing loss (ClinVar). Based on current information, this variant has been classified as PATHOGENIC.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000255988 SCV001334475 pathogenic not provided 2020-02-01 criteria provided, single submitter clinical testing
OMIM RCV000018534 SCV000038816 pathogenic Deafness, autosomal recessive 1A 1998-11-19 no assertion criteria provided literature only
GeneReviews RCV000018534 SCV000041040 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 RCV000477920 SCV000536799 pathogenic Deafness, autosomal recessive 1A; Mutilating keratoderma; Hystrix-like ichthyosis with deafness; Keratitis-ichthyosis-deafness syndrome, autosomal dominant; Palmoplantar keratoderma-deafness syndrome; Knuckle pads, deafness AND leukonychia syndrome; Deafness, autosomal dominant 3a 2016-01-25 no assertion criteria provided research
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678869 SCV000805062 pathogenic Hearing loss 2013-05-22 no assertion criteria provided clinical testing

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