ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.35dup (p.Val13fs) (rs80338939)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169169 SCV000220400 likely pathogenic Deafness, autosomal recessive 1A 2015-02-05 criteria provided, single submitter literature only
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000711350 SCV000700277 pathogenic not provided 2012-08-28 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000609278 SCV000710859 pathogenic Rare genetic deafness 2016-11-30 criteria provided, single submitter clinical testing The p.Val13fs variant in GJB2, also reported as c.35dupG or c.35insG, has been r eported in >5 individuals with hearing loss who were compound heterozygous for a second pathogenic variant in GJB2 (Estivill 1998, Huang 2014, Snoeckx 2005, Tsu kada 2010). It has been identified in 6/250260 of the total chromosomes in the genome Aggregation Database (http://gnomad.broadinstitute.org/, dbSNP rs39812381 4). This low frequency in the general population is consistent with the carrier frequency for autosomal recessive hearing loss. This variant is predicted to ca use a frameshift, which alters the protein?s amino acid sequence beginning at po sition 13 and leads to a premature termination codon 35 amino acids downstream. In summary, this variant meets criteria to be classified as pathogenic for autos omal recessive hearing loss based on the predicted impact to the protein and mul tiple previously reported affected compound heterozygotes.
Athena Diagnostics Inc RCV000711350 SCV000841705 pathogenic not provided 2017-10-17 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169169 SCV000919430 pathogenic Deafness, autosomal recessive 1A 2021-02-09 criteria provided, single submitter clinical testing Variant summary: GJB2 c.35dupG (p.Val13CysfsX35) results in a premature termination codon, predicted to cause a truncation, which is a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2.4e-05 in 249362 control chromosomes (gnomAD). c.35dupG has been reported in the literature in several individuals affected with Autosomal Recessive Non-Syndromic Hearing Loss (e.g. Rabionet_2000, D'Andrea_2002, Dai_2009, Hjelm_2010, Godbole_2010, Bazazzadegan_2012, Usami_2012, Banjara_2015, Liu_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000711350 SCV001148928 uncertain significance not provided 2018-08-01 criteria provided, single submitter clinical testing
GeneDx RCV000711350 SCV001168043 pathogenic not provided 2021-06-08 criteria provided, single submitter clinical testing Observed in other unrelated patients with autosomal recessive nonsyndromic hearing loss in the published literature (Estivill et al., 1998; Yao et al., 2013; Huang et al., 2014); Frameshift variant predicted to result in protein truncation, as the last 214 amino acids are replaced with 34 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: 24503448, 23638949, 9482292, 20639189, 29754767, 31160754, 31541171, 24077912, 27535533, 31589614, 29871260)
Invitae RCV000711350 SCV001400140 pathogenic not provided 2020-08-20 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the GJB2 gene (p.Val13Cysfs*35). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 214 amino acids of the GJB2 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with deafness in a family and it has been reported to be in combination with another GJB2 variant in unrelated individuals affected with deafness (PMID: 23638949, 11439000, 24503448, 18519481, 19366456, 20497192). This variant is also known as 35insG in the literature. ClinVar contains an entry for this variant (Variation ID: 94392). For these reasons, this variant has been classified as Pathogenic.
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000711350 SCV001448869 pathogenic not provided 2016-11-23 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000711350 SCV001480167 pathogenic not provided 2021-02-01 criteria provided, single submitter clinical testing
Department of Otolaryngology – Head & Neck Surgery,Cochlear Implant Center RCV001375474 SCV001572147 likely pathogenic Hearing impairment 2021-04-12 criteria provided, single submitter clinical testing PVS1_Strong, PM2_Moderate, BP5_Supporting
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678861 SCV000805054 pathogenic Hearing loss 2009-01-22 no assertion criteria provided clinical testing
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery,Institute of Otolaryngology, Chinese PLA General Hospital RCV000169169 SCV000902319 pathogenic Deafness, autosomal recessive 1A 2019-02-26 no assertion criteria provided case-control

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