ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.596C>T (p.Ser199Phe) (rs771748289)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169613 SCV000221138 likely pathogenic Deafness, autosomal recessive 1A 2015-02-17 criteria provided, single submitter literature only
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000609655 SCV000710856 pathogenic Rare genetic deafness 2016-09-15 criteria provided, single submitter clinical testing The p.Ser199Phe variant in GJB2 is a common pathogenic variant in the Colombian population, where it has been reported in the homozygous state in 11 individuals with hearing loss (Tamayo 2009). It has also been reported in >15 additional in dividuals with hearing loss who carried a second pathogenic GJB2 variant affecti ng the other allele (Green 1999, Tamayo 2009, Rodriguez-Paris 2011). In vitro fu nctional studies provide some evidence that the p.Ser199Phe variant may impact p rotein function (Xiao 2011, Ambrosi 2013). However, these types of assays may no t accurately represent biological function. This variant has been identified in 1/120100 total chromosomes by the Exome Aggregation Consortium (ExAC, http://exa c.broadinstitute.org; dbSNP rs771748289). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a rec essive carrier frequency. In summary, this variant meets criteria to be classifi ed as pathogenic for hearing loss in an autosomal recessive manner.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169613 SCV000919431 pathogenic Deafness, autosomal recessive 1A 2017-09-11 criteria provided, single submitter clinical testing Variant summary: The GJB2 c.596C>T (p.Ser199Phe) variant involves the alteration of a conserved nucleotide and Ser199 is located in cytoplasmic region (UniProt). 5/5 in silico tools predict damaging outcome for this variant. This variant was found in 1/120100 control chromosomes from ExAC at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.0003376). This variant has been reported in several patients with non-syndromic hearing loss in homozygous as well as in compound heterozygous state with c.35delT and GJB6 deletion and was found to be the most common pathogenic variant in Columbia (Green_1999, Prasad_2000, Azaiez_2004, Snoeckx_2005, Putcha_2007, Tamayo_2009, Rodriguez-Paris_2011). Two independent functional studies showed that this variant leads to defective trafficking (Xiao_2011, Ambrosi_2013). One clinical diagnostic laboratory in ClinVar has classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic.
Athena Diagnostics Inc RCV000991850 SCV001143674 pathogenic not provided 2019-06-14 criteria provided, single submitter clinical testing The best available variant frequency is uninformative because it is below the disease allele frequency. Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Occurs in three or more cases with a recessive pathogenic variant in the same gene. Damaging to protein function(s) relevant to disease mechanism. Moderate co-segregation with disease in multiple families, but using affected individuals only.
Invitae RCV000991850 SCV001202556 likely pathogenic not provided 2020-05-01 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 199 of the GJB2 protein (p.Ser199Phe). The serine residue is highly conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is present in population databases (rs771748289, ExAC no frequency). This variant has been observed in several individuals affected with non-syndromic congenital hearing loss (PMID: 15365987, 19027181). ClinVar contains an entry for this variant (Variation ID: 189183). This variant has been reported to affect GJB2 protein function (PMID: 23967136, 20863150). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000991850 SCV001739925 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000991850 SCV001959713 pathogenic not provided no assertion criteria provided clinical testing
PerkinElmer Genomics RCV000991850 SCV002024271 pathogenic not provided 2021-03-24 no assertion criteria provided clinical testing

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