ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.56G>C (p.Ser19Thr) (rs80338941)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000020575 SCV000599725 uncertain significance Deafness, autosomal recessive 1A 2017-05-09 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000602210 SCV000710858 likely pathogenic Rare genetic deafness 2016-06-28 criteria provided, single submitter clinical testing The p.Ser19Thr variant in GJB2 has been reported in 4 individuals with hearing l oss, 3 of whom were compound heterozygous for a second pathogenic variant in GJB 2, and segregated in one affected family member (Rabionet 2000, Roux 2004, Toth 2004, Gangarossa 2005). This variant has been identified in 2/66716 European chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs80338941); however, its frequency is low enough to be consistent wit h a recessive carrier frequency. In vitro functional studies suggest that the p. Ser19Thr variant may impact protein function (D'Andrea 2002). However, these typ es of assays may not accurately represent biological function. In summary, alth ough additional studies are required to fully establish its clinical significanc e, this variant is likely pathogenic for autosomal recessive hearing loss based on the previously reported compound heterozygous individuals.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000757333 SCV000885517 likely pathogenic not provided 2018-01-08 criteria provided, single submitter clinical testing The GJB2 c.56G>C; p.Ser19Thr variant (rs80338941) has been reported in individuals with hearing loss and has been found in trans with the pathogenic 35delG variant (D'Andrea 2002, Putcha 2007, Rabionet 2000). Functional studies show the variant protein has normal expression but is unable to form functional gap-junction channels in HeLa cells (D'Andrea 2002). This variant is reported in ClinVar (Variation ID: 21389) and observed in the general population with an overall allele frequency of 0.001% (3/244518 alleles) in the Genome Aggregation Database. Based on the above information, this variant is considered likely pathogenic. REFERENCES D'Andrea P et al. Hearing loss: frequency and functional studies of the most common connexin26 alleles. Biochem Biophys Res Commun. 2002 Aug 23;296(3):685-91. Putcha GV et al. A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort. Genet Med. 2007 Jul;9(7):413-26. Rabionet R et al. Molecular basis of childhood deafness resulting from mutations in the GJB2 (connexin 26) gene. Hum Genet. 2000 Jan;106(1):40-4.
GeneReviews RCV000020575 SCV000041051 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 RCV000678862 SCV000805055 pathogenic Hearing loss 2006-12-01 no assertion criteria provided clinical testing

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