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

gnomAD frequency: 0.00002  dbSNP: rs771748289

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169613	SCV000221138	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2015-02-17	criteria provided, single submitter	literature only
Laboratory for Molecular Medicine, Mass General Brigham 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	Autosomal recessive nonsyndromic hearing loss 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	pathogenic	not provided	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 199 of the GJB2 protein (p.Ser199Phe). This variant is present in population databases (rs771748289, gnomAD 0.006%). This missense change has been observed in individuals with autosomal recessive nonsyndromic deafness (PMID: 15365987, 19027181). ClinVar contains an entry for this variant (Variation ID: 189183). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GJB2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GJB2 function (PMID: 20863150, 23967136). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000991850	SCV002024271	pathogenic	not provided	2021-03-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000991850	SCV002577252	pathogenic	not provided	2022-09-13	criteria provided, single submitter	clinical testing	Published functional studies demonstrate impaired membrane targeting, aberrant cellular localization, and intracellular aggregation (Xiao et al., 2011; Ambrosi et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25262649, 10376574, 25388846, 11102979, 15365987, 12408072, 20863150, 25999548, 21738759, 19027181, 25085072, 29311818, 31160754, 31589614, 33297549, 23967136)
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224180	SCV003920012	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A; Mutilating keratoderma; Ichthyosis, hystrix-like, with hearing loss; Autosomal dominant keratitis-ichthyosis-hearing loss syndrome; Palmoplantar keratoderma-deafness syndrome; Knuckle pads, deafness AND leukonychia syndrome; Autosomal dominant nonsyndromic hearing loss 3A	2021-03-30	criteria provided, single submitter	clinical testing	GJB2 NM_004004.5 exon 2 p.Ser199Phe (c.596C>T): This variant has been reported in the literature in the homozygous or compound heterozygous state in numerous individuals affected with autosomal recessive nonsyndromic hearing loss (Green 1999 PMID:10376574, Tamayo 2009 PMID:19027181, Rodriguez-Paris 2011 PMID:21738759). This variant is present in 0.006% (2/34580) of Latino alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/13-20763125-G-A) and is present in ClinVar (Variation ID:189183). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, in vitro functional studies in HeLa cells transfected with S199F have shown a deleterious effect of this variant (Ambrosi 2013 PMID:23967136; Xiao 2011 PMID:20863150). However, these studies may not accurately represent in vivo biological function. In summary, this variant is classified as pathogenic based on the data above.
PreventionGenetics, part of Exact Sciences	RCV003407629	SCV004114723	pathogenic	GJB2-related condition	2023-06-06	criteria provided, single submitter	clinical testing	The GJB2 c.596C>T variant is predicted to result in the amino acid substitution p.Ser199Phe. This variant has been reported as pathogenic for autosomal recessive hearing loss (Green et al 1999. PubMed ID: 10376574; Table S4, Shearer et al. 2014. PubMed ID: 25262649; 2015. PubMed ID: 25388846; García-García et al. 2020. PubMed ID: 33297549; Rodriguez-Paris et al. 2011. PubMed ID: 21738759), and functional experiments have demonstrated aberrant GJB2 protein localization to the cytoplasm (Ambrosi et al. 2013. PubMed ID: 23967136). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-20763125-G-A). This variant is interpreted as pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000991850	SCV001739925	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000991850	SCV001959713	pathogenic	not provided		no assertion criteria provided	clinical testing