ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.235del (p.Leu79fs) (rs80338943)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel, RCV000211768 SCV000840502 pathogenic Nonsyndromic hearing loss and deafness 2018-09-14 reviewed by expert panel curation The filtering allele frequency of the p.Leu79CysfsX3 variant in the GJB2 gene is 0.55% (121/ 18870) of East Asian 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 hearing loss variants (BS1). 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 BS1 code will not contribute to the overall classification. The p.Leu79CysfsX3 variant in GJB2 is predicted to cause a premature stop codon in the only exon of the gene, leading to absent protein in a gene in which loss-of-function is an established 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: 10983956, 10633133). A dye transfer assay, a functional study, has shown that the variant impacts protein function (PS3_M; PMID: 12352684). 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, PS3_M, BS1.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000844630 SCV000061489 pathogenic Rare genetic deafness 2012-02-10 criteria provided, single submitter clinical testing The c.235delC variant in GJB2 is a well-studied pathogenic variant (Abe 2000, Pa rk 2000, Choung 2002, Liu 2002, Ohtsuka 2003, Yao 2012). This variant is predict ed to cause a frameshift, which alters the protein's amino acid sequence beginni ng at codon 79 and leads to a premature termination codon 3 amino acids downstre am. This alteration is then predicted to lead to a truncated or absent protein. In summary, this variant meets criteria to be classified as pathogenic for heari ng loss in an autosomal recessive manner. ACMG/AMP Criteria applied: PVS1, PM3_ VeryStrong.
Genetic Services Laboratory, University of Chicago RCV000146011 SCV000193162 pathogenic Hearing impairment 2013-02-08 criteria provided, single submitter clinical testing
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000490501 SCV000267340 pathogenic Deafness, autosomal recessive 1A; Deafness, autosomal dominant 3a 2016-03-18 criteria provided, single submitter reference population
GeneDx RCV000255303 SCV000322427 pathogenic not provided 2018-05-14 criteria provided, single submitter clinical testing The c.235delC variant in the GJB2 gene is one of the most common variants reported in the GJB2 gene, with a carrier frequency of 1-2% in the Japanese and Chinese populations (Fuse et al., 1999; Dzhemileva et al., 2010; Yao et al., 2012). The c.235delC variant has been reported previously, either in the homozygous state or in trans with a second pathogenic variant, in association with autosomal recessive nonsyndromic hearing loss (Fuse et al., 1999; Putcha et al., 2007; Yao et al., 2012). The c.235delC variant causes a frameshift starting with codon Leucine 79, changes this amino acid to a Cysteine residue, and creates a premature Stop codon at position 3 of the new reading frame, denoted p.Leu79CysfsX3. This variant is predicted to cause loss of normal protein function through protein truncation. Functional studies indicate that cells expressing c.235delC fail to reach their destination in the cell membrane and have reduced gap junction activity (Choung et al., 2002; Zhang et al., 2010). We interpret c.235delC as a pathogenic variant.
Counsyl RCV000018538 SCV000487397 pathogenic Deafness, autosomal recessive 1A 2016-03-08 criteria provided, single submitter clinical testing
Counsyl RCV000410166 SCV000487398 pathogenic Deafness, autosomal dominant 3a 2016-03-08 criteria provided, single submitter clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000018538 SCV000599737 pathogenic Deafness, autosomal recessive 1A 2017-05-09 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000255303 SCV000603827 pathogenic not provided 2017-06-09 criteria provided, single submitter clinical testing The GJB2 c.235delC; p.Leu79fs variant (rs80338943) creates a frameshift and is predicted to result in a truncated protein or absent transcript. This variant is a well-studied pathogenic variant associated with autosomal recessive nonsyndromic hearing loss (see link, Choung 2002, Du 2016, Fuse 1999, Han 2008, Zhang 2010). REFERENCES Link to ClinVar database for c.235delC: https://www.ncbi.nlm.nih.gov/clinvar/variation/17014/ Choung YH et al. Functional study of GJB2 in hereditary hearing loss. Laryngoscope. 2002 Sep;112(9):1667-71. Du Y et al. Analysis of p.V37I compound heterozygous mutations in the GJB2 gene in Chinese infants and young children. Biosci Trends. 2016 Jul 19;10(3):220-6. Fuse Y et al. Three novel connexin26 gene mutations in autosomal recessive non-syndromic deafness. Neuroreport. 1999 Jun 23;10(9):1853-7. Han SH et al. Carrier frequency of GJB2 (connexin-26) mutations causing inherited deafness in the Korean population. J Hum Genet. 2008;53(11-12):1022-8. Zhang Y et al. Three common GJB2 mutations causing nonsyndromic hearing loss in Chinese populations are retained in the endoplasmic reticulum. Acta Otolaryngol. 2010 Jul;130(7):799-803.
Athena Diagnostics Inc RCV000255303 SCV000613508 pathogenic not provided 2015-07-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000018538 SCV000698238 pathogenic Deafness, autosomal recessive 1A 2016-05-10 criteria provided, single submitter clinical testing Variant summary: The GJB2 c.235delC (p.Leu79Cysfs) variant results in a premature termination codon, predicted to cause a truncated or absent GJB2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Mutation taster predicts a damaging outcome for this variant. It was found in 44/121376 control chromosomes at a frequency of 0.0003625, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). The variant was reported in several autosomal recessive non-syndromic hearing loss patients either in homozygosity or in compound heterozygosity with other pathogenic GJB2 variants indicating pathogenicity. Additionally, a functional study demonstrated the variant to result in a truncated form of GJB2 which is not capable to facilitate junctional conductance, further supporting a deleterious impact. Moreover, multiple clinical diagnostic laboratories classified this variant as Pathogenic. Taken together, this variant is classified as pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000255303 SCV000700278 pathogenic not provided 2017-12-21 criteria provided, single submitter clinical testing
Invitae RCV000255303 SCV000938184 pathogenic not provided 2018-12-22 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the GJB2 gene (p.Leu79Cysfs*3). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 148 amino acids of the GJB2 protein. This variant is present in population databases (rs80338943, ExAC 0.5%). This variant has been reported as homozygous or compound heterozygous in many individuals and families affected with autosomal recessive non-syndromic hearing loss (PMID: 10501520, 27045574, 20739944, 22747691, 15479191, 26061264, 25266519, 17505205) and is a well known founder in the Asian population (PMID: 14505035). This variant is also known as c.233delC in the literature. ClinVar contains an entry for this variant (Variation ID: 17014). Experimental studies have shown that this frameshift change results in GJB2 protein being trapped in the endoplasmic reticulum, failing to be expressed in the plasma membrane and therefore, causing severe deterioration of gap junction activity (PMID: 12352684, 20095872). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000018538 SCV000038820 pathogenic Deafness, autosomal recessive 1A 2009-02-01 no assertion criteria provided literature only
OMIM RCV000018539 SCV000038821 pathogenic Deafness, digenic, GJB2/GJB3 2009-02-01 no assertion criteria provided literature only
GeneReviews RCV000018538 SCV000041042 pathologic Deafness, autosomal recessive 1A 2011-07-14 no assertion criteria provided curation Converted during submission to Pathogenic.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678874 SCV000805067 pathogenic Hearing loss 2015-03-20 no assertion criteria provided clinical testing
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery,Institute of Otolaryngology, Chinese PLA General Hospital RCV000018538 SCV000902316 pathogenic Deafness, autosomal recessive 1A 2019-02-26 no assertion criteria provided case-control

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