ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.176_191del (p.Gly59fs) (rs750188782)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000725553 SCV000337719 pathogenic not provided 2015-11-24 criteria provided, single submitter clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000374903 SCV000599736 pathogenic Deafness, autosomal recessive 1A 2017-05-09 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000374903 SCV000917455 pathogenic Deafness, autosomal recessive 1A 2020-12-10 criteria provided, single submitter clinical testing Variant summary: GJB2 c.176_191del16 (p.Gly59AlafsX18) 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. The variant allele was found at a frequency of 1.6e-05 in 252656 control chromosomes (gnomAD and publications). c.176_191del16 has been reported in the literature in multiple individuals affected with Autosomal Recessive Non-Syndromic Hearing Loss, in both compound heterozygous and homozygous states (e.g. Abe_2000, Kudo_2000, Snoeckx_2005, Dai_2009, Miyagawa_2013, Shi_2018). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function, showing that the mutant protein was unable to form gap junctions with the plasma membrane, leading to retention in the endoplasmic membrane (ER) and suggesting that ER stress (ERS) and subsequent ERS-induced cell death may be reponsible for the hearing loss associated with this mutation (e.g. Zhang_2010, Shi_2018). Seven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000725553 SCV000951165 pathogenic not provided 2020-10-18 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the GJB2 gene (p.Gly59Alafs*18). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 168 amino acids of the GJB2 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in many individuals with autosomal recessive nonsyndromic hearing loss, and is commonly found in affected individuals of East Asian descent (PMID: 10633133, 19125024, 19366456, 24224790, 26043044). ClinVar contains an entry for this variant (Variation ID: 284906). Experimental studies have shown that this variant results in a truncated protein produce that does not localize properly when expressed in cell culture (PMID: 20095872). This variant disrupts the C-terminus of the GJB2 protein. Other variant(s) that disrupt this region (such as p.Leu79Cysfs*3 and p.Tyr97*) have been determined to be pathogenic (PMID: 15070423, 19371219, 22747691, 26061264). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics Inc RCV000725553 SCV001143661 pathogenic not provided 2018-11-14 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 RCV001000906 SCV001157989 pathogenic not specified 2018-11-07 criteria provided, single submitter clinical testing The GJB2 c.176_191del; p.Gly59fs variant (rs750188782) is associated with autosomal recessive nonsyndromic hearing loss (Abe 2000, Davoudi-Dehaghani 2014, Han 2008, Zhang 2010) and is reported as one of the most common pathogenic GJB2 variants in Chinese populations (Zhang 2010). This variant is classified as pathogenic in ClinVar (Variation ID: 284906). It is found in the general population with an overall allele frequency of 0.001% (3/246064 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting 16 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. Davoudi-Dehaghani E et al. Reporting the presence of three different diseases causing GJB2 mutations in a consanguineous deaf family. Int J Audiol. 2014 Feb;53(2):128-31. 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.
GeneDx RCV000725553 SCV001790968 pathogenic not provided 2020-12-02 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation, as the last 168 amino acids are replaced with 17 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 29871260, 30275481, 31541171, 31564438, 30146550, 30036422, 30693673, 29665173, 30589569, 30282152, 19366456, 25388846, 28489599, 28583500, 29741433, 10607953, 26037344, 19125024, 24100002, 24737404, 26043044, 19043807, 10633133, 24224790, 25266519, 20095872)
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery,Institute of Otolaryngology, Chinese PLA General Hospital RCV000374903 SCV000902314 pathogenic Deafness, autosomal recessive 1A 2019-02-26 no assertion criteria provided case-control
Counsyl RCV000374903 SCV001132399 likely pathogenic Deafness, autosomal recessive 1A 2015-03-23 no assertion criteria provided clinical testing
Natera, Inc. RCV000374903 SCV001453347 pathogenic Deafness, autosomal recessive 1A 2020-09-16 no assertion criteria provided clinical testing

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