ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.508_511dup (p.Ala171fs) (rs773528125)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169473 SCV000220917 likely pathogenic Deafness, autosomal recessive 1A 2014-11-25 criteria provided, single submitter literature only
Genetic Services Laboratory, University of Chicago RCV000169473 SCV000247476 pathogenic Deafness, autosomal recessive 1A 2013-02-08 criteria provided, single submitter clinical testing
GeneDx RCV000498375 SCV000589636 pathogenic not provided 2019-01-18 criteria provided, single submitter clinical testing The c.508_511dupAACG pathogenic variant in the GJB2 gene has been reported previously in association with non-syndromic autosomal recessive hearing loss (Hismi et al., 2006; Zhu et al., 2015). The variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The duplication causes a frameshift starting with codon Alanine 171, changes this amino acid to a Glutamic acid residue and creates a premature Stop codon at position 40 of the new reading frame, denoted p.Ala171GlufsX40. This pathogenic variant is predicted to cause loss of normal protein function through protein truncation.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000169473 SCV000599756 pathogenic Deafness, autosomal recessive 1A 2017-05-09 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169473 SCV000698264 pathogenic Deafness, autosomal recessive 1A 2017-04-13 criteria provided, single submitter clinical testing Variant summary: The GJB2 c.508_511dupAACG (p.Ala171Glufs) 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. One truncation downstream of this position has been classified as pathogenic by our laboratory (c.647_650delGATA/ p.Arg216fs). One in silico tool predicts a damaging outcome for this variant. The variant of interest has been found in a large, broad control population, ExAC in 2/121034 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.0003376). This variant has been reported in multiple studies, in Chinese and Koreean populations with NSHL in the compound heterozygous and homozygous state (Zhu_2015, Kim_2015, Jiang_2014). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000498375 SCV000701343 pathogenic not provided 2016-07-20 criteria provided, single submitter clinical testing
Invitae RCV000498375 SCV001225144 pathogenic not provided 2020-10-01 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the GJB2 gene (p.Ala171Glufs*40). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 56 amino acids of the GJB2 protein. This variant is present in population databases (rs773528125, ExAC 0.02%). This variant has been observed in several individuals affected with sensorineural hearing loss (PMID: 12172394, 25891447). This variant is also known as 511-512insAACG in the literature. ClinVar contains an entry for this variant (Variation ID: 189070). This variant disrupts the C-terminus of the GJB2 protein. Other variant(s) that disrupt this region (p.Cys211Leufs*5) have been determined to be pathogenic (PMID: 9529365, 12910486, 20863150). 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.
Nilou-Genome Lab RCV000169473 SCV001810445 pathogenic Deafness, autosomal recessive 1A 2021-07-22 criteria provided, single submitter clinical testing
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery,Institute of Otolaryngology, Chinese PLA General Hospital RCV000169473 SCV000902320 pathogenic Deafness, autosomal recessive 1A 2019-02-26 no assertion criteria provided case-control
Natera, Inc. RCV000169473 SCV001463361 pathogenic Deafness, autosomal recessive 1A 2020-09-16 no assertion criteria provided clinical testing

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