ClinVar Miner

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

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Total submissions: 7
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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.
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000169473 SCV000599756 pathogenic Deafness, autosomal recessive 1A 2017-05-09 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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
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

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